Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in Colombia

Wilmer A Cárdenas; Andrew B Conley; Shashwat Deepali Nagar; Diana L Núñez-Ríos; I King Jordan; María Claudia Lattig

doi:10.1371/journal.pone.0313777

. 2024 Nov 18;19(11):e0313777. doi: 10.1371/journal.pone.0313777

Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in Colombia

Wilmer A Cárdenas ¹, Andrew B Conley ², Shashwat Deepali Nagar ^2,³, Diana L Núñez-Ríos ^4,^*, I King Jordan ^2,³, María Claudia Lattig ¹

Editor: Arnar Palsson⁵

PMCID: PMC11573203 PMID: 39556609

Abstract

Autosomal recessive conditions are often associated with homozygous mutations showing common ancestral origins and are frequently linked to consanguinity. However, an increasing number of compound heterozygotes are found in diverse, admixed populations. Oculocutaneous albinism (OCA) is a recessive condition caused mainly by mutations in the TYR and OCA2 genes involved in skin pigmentation. We previously screened the TYR and OCA2 genes in Colombian OCA families, identifying both known and novel mutations. Affected family members were found to be either homozygous or compound heterozygous for these gene mutations. Compound heterozygosity, where two different recessive alleles inherited from each parent lead to the expression of an autosomal recessive trait, poses a challenge in genetic diagnosis. Estimating the ancestry of these disease-associated variants, in conjunction with understanding the colonization history of admixed populations, can enhance the precision of association mapping in genetic studies. The aim of this study was to determine the ancestral origins of TYR and OCA2 mutations for OCA patients from two populations located in the Andes region of Colombia–Altiplano Cundiboyacense and Marinilla-Santuario. Comparison of OCA patients, and their unaffected relatives, with global reference populations showed a pattern of European and Native American admixture, with little African ancestry, for these two populations. Mutation-bearing TYR and OCA2 haplotypes from Colombian OCA patients were compared against haplotypes from Spanish, Native American, and Sephardic Jewish reference populations to infer their ancestral origins. For 12 OCA1 patients from the Altiplano Cundiboyacense region, 21 out of 24 mutated TYR haplotypes show Spanish origins, two show Native American origins, and one shows a Sephardic Jewish origin. The two Native American TYR haplotypes, and the single Sephardic Jewish haplotype, are all found in compound heterozygote patients, paired with the predominant Spanish TYR haplotype G47D. OCA in these three patients is a result of genetic admixture that brought together disease-causing mutations with distinct ancestral origins. Both OCA2 patients from the Marinilla-Santuario region show homozygous OCA2 mutations with a Spanish origin. These findings underscore the complexity of the genetic architecture of Mendelian disease in admixed American populations, with both consanguinity and admixture contributing to the risk of autosomal recessive OCA in Colombia.

Introduction

Colombia has a highly admixed population with African, European, and Native American ancestry components [1–4]. Prior to the arrival of Spanish conquistadors in 1525, Colombia was populated by various Native American groups, including the Muisca who inhabited the central Andean highland region (corresponding to the modern departments of Boyacá and Cundinamarca) and the Quimbaya who inhabited the Cauca river valley to the west and south (corresponding to the modern departments of Caldas, Quindío, and Risaralda) [5]. The early period of Spanish colonization resulted in European and Native American admixture, which was sex-biased with predominantly male European and female Native American components, and later the transatlantic slave trade introduced an African ancestry component [1, 4, 6–9]. A smaller number of Conversos–Sephardic Jews who converted to Catholicism owing to persecution in Spain and Portugal–also immigrated to Colombia in the 16th and 17th centuries, and a subsequent wave of Jewish immigration to Colombia occurred during and after World War II [10–12].

The degree of African, European, and Native American admixture varies among the five natural regions of Colombia: Amazonian, Andean, Caribbean, Orinoquian, and Pacific [13]. This study is focused on the Andean region, which is characterized by relatively high levels of European and Native American ancestry compared to low levels of African ancestry [11, 14, 15]. Discernable levels of Converso genetic ancestry were also recently discovered in Colombian populations sampled from this region [11]. To date, the vast majority of clinical genomics research has been conducted on European ancestry participant cohorts, with genomes from Latin America being particularly underrepresented [16–18]. For example, as of May 2024, the genome-wide association study (GWAS) diversity monitor shows that Hispanic or Latin American individuals make up a mere 0.38% of GWAS study participants [19]. The Eurocentric bias in genomics research limits the global reach of precision medicine and obscures the impact of human migration and evolution on genetic disease. We are interested in the relationship between genetic ancestry, admixture, and the presence of mutations that cause oculocutaneous albinism (OCA) in Colombian populations from the Andean region. The populations studied here live in the Andean areas of Altiplano Cundiboyacense and Antioquia, which are located in the eastern (cordillera oriental) and central (cordillera central) Andes mountain ranges, respectively, separated by the Magdalena River (Fig 1A).

Fig 1 — (A) Locations of Altiplano Cundiboyacense (white) and Marinilla-Santuario (red) in the Colombian administrative departments of Boyacá (blue), and Antioquia (yellow). The map file used to generate the image is freely distributed for MapSVG and is licensed under the Creative Commons Attribution 4.0 International Public License (URLs: https://mapsvg.com/maps/world and https://mapsvg.com/maps/colombia). (B) Principal component analysis (PCA) projection of genomic distances between Colombian and global reference populations. (C) ADMIXTURE plot showing African (blue), European (yellow), and Native American (red) ancestry fractions for individuals from Colombian and global reference populations.

There are two subtypes of OCA; OCA1 (type I) is caused by mutations in the tyrosinase gene (TYR), and OCA2 (type II) is caused by mutations in the OCA2 melanosomal transmembrane protein gene (OCA2) [20, 21]. OCA1 is characterized by extremely pale skin, white hair, and light-colored irises, whereas OCA2 is typically less severe than OCA1 and characterized by creamy white colored-skin and hair that can be light yellow, blond, or light brown. We previously described seven different mutations in the TYR gene responsible for OCA1 in individuals from Altiplano Cundiboyacense and a single OCA2 mutation responsible for OCA2 in individuals from towns of Marinilla and Santuario in Antioquia [22, 23]. The most common TYR mutation observed in Altiplano Cundiboyacense was G47D (dbSNP rs61753180) found in 82% of OCA1 cases. The G47D mutation was found as homozygous or as compound heterozygous together with either the 1379delTT, 580delA, or S184X mutations of the same TYR gene. A787T (dbSNP: rs2063883437) was the only OCA2 mutation found in the Antioquia towns of Marinilla and Santuario, where high numbers of individuals with OCA2 reside.

Given the ancestral diversity of Colombian populations, together with our previous observations of TYR compound heterozygotes in Altiplano Cundiboyacense, we hypothesized that admixture resulting from the Spanish colonization of Colombia may have led to multiple OCA mutations of distinct ancestries segregating in individuals from the Andean region. We refer to this phenomenon as the admixture-derived compound heterozygote hypothesis [24, 25]. In support of this idea, the G47D mutation was suggested to have a Sephardic Jewish origin based on its high prevalence among Moroccan Jews living in Israel [26]. This same mutation was found in OCA patients living in the Canary Islands and Puerto Rico, suggesting the possibility of a common origin linked to the Sephardic Jewish diaspora [26, 27]. Given the potential admixture-derived compound heterozygote observed in families from the Andean regions, along with the reported origin of OCA mutations and Colombia’s history of multiple waves of immigration from various ancestral groups (including Spanish and Jewish populations), we decided to perform haplotype inference analysis for each of the previously reported OCA-related mutations. Through this analysis, we aim to provide valuable insights into the genetic complexities of admixed populations, including the development of autosomal recessive conditions due to genetic admixture and the influence of inbreeding and outbreeding depression on mating patterns among unrelated individuals.

Methods

Study cohort and ethics

The study cohort consists of 19 individuals who were enrolled in March 2017 and sampled for a prior study on the genetic etiology of OCA in Colombia [22, 23]. Our initial study included 36 individuals with OCA from 23 independent families across various Colombian regions, recruited through the Albino Organization ’Fundación Contraste–Albinos por Colombia [22, 23]. The current study includes nine individuals from a single family in Altiplano Cundiboyacense, including four OCA1-affected and five unaffected individuals. Eight additional unrelated OCA1-affected individuals were sampled from Altiplano Cundiboyacense and nearby departments. Two unrelated OCA2-affected individuals were sampled from in or nearby the Marinilla-Santuario region in Antioquia (Fig 1A). The same pedigree data and nomenclature reported by our group [22, 23] are preserved in this study.

This study conforms to the Helsinki ethical principles for medical research involving human subjects. The Albinism project was evaluated and approved by the Universidad de los Andes Research Ethics Committee and determined to comply with all scientific, technical, and administrative standards for health research established by the 1993 Resolution #008430 of the Colombian Ministry of Health. The project was classified as minimal risk by the ethics committee. Participant recruitment was done in collaboration with local community representatives, and vulnerable individuals were excluded from participation. All participants or their legal guardians signed informed consent, indicating their understanding of the genetic testing procedure, the benefits, limits, and possible consequences of the test, and granting permission for basic genetic research to be conducted on their samples. Access to participant samples was restricted to the project principal investigator (MCL).

Genetic variant analysis

DNA samples were accessed in March 2017. TYR and OCA2 mutations from participant samples were examined using Sanger sequencing as described in previous studies on these individuals [22, 23]. The identities of pathogenic mutations were confirmed based on disease diagnosis, previous OCA literature, the ClinVar and OMIM databases, and patterns of inheritance (homozygous or compound heterozygous).

These individuals were genotyped with the Infinium OmniExpress-24 BeadChip (Illumina) using the Macrogen service (Seoul, Republic of Korea). The 24 Omni Express Chip evaluates genotypes at ~720,000 sites genome-wide. Genome-wide genotype data from the Colombian cohort were merged and harmonized with genomic variant data from global reference samples to facilitate genetic ancestry inference. The ancestry of TYR haplotypes was evaluated using a 318kb region, +/- 100kb from the gene transcription start and end sites (chr11:89,077,875–89,395,759), consisting of 47 SNPs. African (YRI, n = 108), European (IBS, n = 107) and Native American (PEL, n = 85) ancestry reference samples, along with a Colombian population from Medellín (CLM, n = 94), were from the 1000 Genomes Project [28]. Genomic variant data from Sephardic Jewish populations (JWS, n = 121) were taken from a study on Jewish genetic ancestry [29]. Genomic variant merging and harmonization were done using PLINK version 1.9 and custom scripts [30]. A variant missingness filter of 5% was used together with a minor allele frequency filter of 1%. Linkage disequilibrium pruning was performed using the “-indep” command in PLINK 1.9 with a window size of 50 kb, a step size of 5 variants, and a variant inflation factor threshold of 2. Phasing was performed using ShapeIT version 2.r837 [31].

Genetic ancestry inference

The merged and harmonized genomic variant dataset was used for genome-wide and local (i.e. haplotype around the TYR and OCA genes) ancestry inference. Principal component analysis was performed to examine ancestry divergence via comparison with genomic variant data from African, European, and Native American reference populations by using “-pca” option in PLINK version 1.9. Genome-wide ancestry inference was performed using the program ADMIXTURE version 1.30 [32]. Local ancestry inference, i.e. the assignment of ancestral origins for individual haplotypes across the genome, was performed using RFMix version 2 [33]. TYR and OCA2 haplotype regions were operationally defined as ±50kb from the start and stop site of each gene, and haplotype ancestral origins were taken from RFMix output. Ancestry origins were only considered when the RFMix ancestral certainty was at least 95%. TYR haplotype sequences were extracted and analyzed using MEGA version X to visualize haplotype relationships [34]. Pairwise identity-by-state distances were computed for all pairs of TYR haplotypes, and the resulting distance matrix was used to reconstruct a neighbor-joining phylogeny [35].

Results

Genetic ancestry and admixture of Colombian OCA patients

Principal component analysis (PCA) shows that the Colombian OCA patients studied here group closely together and fall between the European and Native American reference populations along principal component 2 (PC2; Fig 1B). The Colombian OCA patients are more tightly grouped in PCA spaced compared to a previously studied Colombian population from Medellín in Antioquia, which extends further towards the European reference population along PC2 and slightly towards the African reference population along PC1. Genetic admixture analysis, using the same global reference populations, confirmed that the Colombian OCA patients have a more even two-way European and Native American admixture pattern compared to the previously studied Colombian population from Medellín (Antioquia), which shows greater overall variation in admixture, with relatively more European and African ancestry and less Native American ancestry (Fig 1C).

Ancestral origins of TYR and OCA2 mutations

Next, TYR and OCA2 haplotypes for Colombian OCA patients were compared to orthologous haplotypes from Spanish, Native American, and Sephardic Jewish reference populations to infer their ancestral origins. Pairwise identity-by-state distances were calculated between haplotypes and used to reconstruct haplotype phylogenies as illustrated for a subset of TYR haplotypes in Fig 2. The TYR G47D haplotype was inferred to have a Spanish origin owing to its sequence identity with Spanish-origin haplotypes sampled from Spanish (IBS) and Peruvian (PEL) populations. The TYR 1379delTT haplotype was inferred to have Native American origins by its clustering within a clade of Native American origin haplotypes sampled from a Peruvian population. The Spanish-origin G47D haplotype is found in 21 out of the 24 mutated TYR haplotypes among the 12 OCA1 patients evaluated here (Table 1). Two of the four affected family members were confirmed to be G47D homozygous, one was found to be G47D-1379delTT compound heterozygous, and one was characterized as G47D with a second unknown mutation. The individual with the second unknown mutated TYR haplotype is likely to be G47D homozygous based on the Spanish origin of that second haplotype. Three out of eight of the unrelated OCA1 patients were G47D homozygous, and three were found to be G47D-D42N compound heterozygous. The D42N haplotype also shows a Spanish origin.

Fig 2 — Neighbor-joining phylogeny based on pairwise genetic distances between TYR gene haplotypes. The Colombian G47D and 1379delTT haplotypes are shown along with their most closely related reference haplotypes. Reference haplotypes are color-coded according to their ancestral (population) origins as shown.

Table 1. TYR and OCA2 mutations and haplotype origins.

Pedigree^a	Gene	Genotype^b	Region	Haplotype Origin	Phenotype^c
*Family with OCA1 (TYR* gene)**
VI-29	TYR	G47D \| 1379delTT	Altiplano Cundiboyacense	Spanish\| Native American	Complete albinism
VI-28	TYR	WT \| WT	Altiplano Cundiboyacense	Spanish\| Native American	Without albinism
VI-30	TYR	WT \| 1379delTT	Altiplano Cundiboyacense	Native American \| Native American	Without albinism
VI-1	TYR	Unknown \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
V-19	TYR	G47D \| WT	Altiplano Cundiboyacense	Spanish\| Native American	Without albinism
V-20	TYR	WT \| 1379delTT	Altiplano Cundiboyacense	Spanish\| Native American	Without albinism
V-26	TYR	G47D \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
V-27	TYR	G47D \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
IV-11	TYR	WT \| G47D	Altiplano Cundiboyacense	Native American \| Spanish	Without albinism
*Unrelated individuals with OCA1 (TYR* gene)**
	TYR	G47D \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
	TYR	G47D \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
	TYR	G47D \| G47D	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
	TYR	G47D \| D42N	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
	TYR	G47D \| D42N	Altiplano Cundiboyacense	Spanish \| Spanish	Complete albinism
	TYR	G47D \| D42N	Meta	Spanish \| Spanish	Complete albinism
	TYR	G47D \| 580delA	Nariño	Spanish\| Native American	Complete albinism
	TYR	G47D \| S184X	Tolima	Spanish\| Sephardic Jewish	Complete albinism
*Unrelated individuals with OCA2 (OCA2* gene)**
	OCA2	A787T \| A787T	Marinilla-Santuario	Spanish \| Spanish	Partial albinism
	OCA2	A787T \| A787T	Caldas	Spanish \| Spanish	Partial albinism

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^a Pedigree code for individual family members as shown in Fig 3.

^b Amino acid changes are shown with the protein-level mutation code, with the affected amino acid (one-letter code), its position, and the mutated amino acid. DNA-level deletions are shown with the position and the deleted nucleotides. WT refers to wild-type sequences with no albinism-causing mutation.

^c Complete albinism refers to the more severe OCA1 (type I) associated phenotype, and partial albinism refers to the milder OCA1 (type II) associated phenotype.

The remaining two unrelated OCA1 individuals were compound heterozygotes, where each haplotype had a distinct ancestral origin. One of these individuals has a combination of the predominant Spanish-origin G47D haplotype and a second Native American-origin 580delA mutated haplotype, and the other individual had a combination of the predominant Spanish-origin G47D haplotype and a Sephardic Jewish-origin S184X haplotype. Both of the unrelated OCA2 patients evaluated here were homozygous for the Spanish-origin A787T OCA2 haplotype.

The pedigree in Fig 3 shows the inheritance patterns and ancestral origins for OCA1 causing TYR mutations, and the haplotypes on which they reside, in a single Colombian family. The inheritance patterns and haplotype origins for three out of the four affected individuals (V-26, V-27, and V-29) can be inferred based on the pedigree, whereas the fourth affected individual (VI-1) has an unknown inheritance and one uncharacterized mutated haplotype. Affected individuals V-26 and V-27 are siblings who inherited Spanish-origin G47D haplotypes from each of their unaffected (heterozygous) parents. Affected individual VI-29 is a compound heterozygote with a paternally inherited Spanish origin G47D haplotype and a maternally inherited Native American origin 1379delTT haplotype.

Discussion

Our study on the genetic etiology of OCA in Colombia highlights the valuable insights that can be obtained from clinical genomics studies of Latin American populations with significant genetic admixture. Colombia serves as an ideal setting for studies like this one aimed at exploring the relationship between ancestry, admixture, and genetic determinants of health. The Colombian population has African, European, and Native American ancestry components, with distinct admixture patterns seen for different regions in the country [1–4, 6–9, 11, 14, 15]. African genetic ancestry is highest in the Pacific and Caribbean regions, whereas Native American ancestry is highest in the Amazonian and Orinoquian regions. The study population in the Andean region, mainly has European and Native American ancestry, and as the data revealed, a notable Converso ancestry component (Fig 1) [11].

OCA, an autosomal recessive condition, exhibits variable prevalence rates globally, ranging from 1 in 1,755 to 1 in 15,000 individuals [36]. Our group previously reported an elevated number of OCA cases in small towns within the Colombian Andean region [22, 23]. Furthermore, affected individuals carry mutations with unknown global frequencies in the gnomAD database [37] and exhibit compound heterozygosity. Here, examining relationship between genetic ancestry, admixture, and pattern of OCA mutation in Colombia, we found OCA1 patients from our Altiplano Cundiboyacense study population show TYR mutations with ancestral origins from all three of these groups (Fig 2 and Table 1). The Spanish-origin G47D mutation is the most common, found in 21 out of 24 OCA1-linked haplotypes studied here, and there are two distinct Native American-origin TYR mutations and a single Sephardic Jewish-origin TYR mutation. All three of the non-Spanish-origin TYR mutations are found as compound heterozygotes in combination with the predominant Spanish-origin G47D mutation. The two OCA2 patients from the Marinilla-Santuario region show a single Spanish-origin OCA2 mutation A787T.

It was previously proposed that the G47D haplotype had a Sephardic Jewish origin [27], but here we demonstrate a Spanish origin for this haplotype (Fig 2 and Table 1). Considered together with the presence of G47D mutations in the Canary Islands and Puerto Rico [26], our finding is consistent with G47D as a founder mutation that was established in Colombia by Spanish migration and colonization in the New World. The G47D founder mutation in Altiplano Cundiboyacense could be linked to the small founding population of Spanish colonizers who settled in the town of Ciénega, in an area previously inhabited by the Muisca, located in the modern department of Boyacá. It should be stressed that these two views on the origins of the G47D mutation may not be mutually exclusive. Sephardic Jews are a Jewish diaspora population from the Iberian Peninsula, who were eventually exiled from Spain following the Alhambra Decree of 1492 and fled to North Africa [38]. Thus, the presence of the G47D haplotype among Moroccan Jews in Israel could be attributed to the exile of Sephardic Jews from 15th-century Spain to Morocco followed by a subsequent expulsion from Morocco and migration to Palestine in the 19th century or the modern state of Israel in the 20th century.

The two OCA2 patients from Marinilla-Santuario evaluated here are both homozygous with Spanish-origin A787T mutations. This observation and the previous finding that the Marinilla-Santuario region had the highest inbreeding coefficient in Colombia [39], is consistent with the idea that a founder event influenced variation in this region in particular. However, given the relatively low sample size of two Marinilla-Santuario samples, and the lack of pedigree linking these samples, this conclusion is not as well supported as the G47D founder mutation.

The pedigree shown in Fig 3 underscores the complex inheritance patterns for OCA1-linked TYR mutations in a single Colombian family. There are three OCA patients in this pedigree, for which both TYR mutations and haplotype origins are analyzed. Two of these individuals, who are siblings, are homozygous for the same G47D haplotype inherited from both parents, pointing to some degree of consanguinity in this family. This is consistent with a known role for consanguinity in many autosomal recessive disorders [40, 41], such as thalassemia, cystic fibrosis, and Tay-Sachs disease, and represents a kind of inbreeding depression where reduced fitness of individuals with genetically related parents is caused by recessive deleterious mutations that are identical by descent [42].

In contrast to the presumed OCA founder effect mutations seen for the TYR and OCA2 genes, one of the Altiplano Cundiboyacense family members shown in Fig 3, and two of the eight unrelated OCA patients from Altiplano Cundiboyacense, also show evidence for compound heterozygous mutations with distinct ancestral origins. Two of these cases show Spanish-Native American haplotype combinations and one shows a Spanish-Sephardic Jewish haplotype combination (Table 1). These cases point to a role for genetic admixture in generating disease-causing compound heterozygotes, which could represent an example of outbreeding depression in humans [43, 44]. This diversity of haplotype combinations is consistent with the larger population of the Altiplano Cundiboyacense region, compared to Marinilla-Santuario, including the capital city of Bogotá, which has a large and ethnically diverse population of ~8 million inhabitants.

The interplay between deleterious variants, genetic admixture, and inbreeding has been documented in Antioquia—Colombia, particularly in relation to complex disorders like Alzheimer’s disease, frontotemporal lobar degeneration and early-onset dementia. A case of early-onset Alzheimer’s disease was identified in an individual who was a compound heterozygote, carrying both the African-origin Thr96Lys/Trp191*/Leu211Pro haplotype and the Native American c.469C>T (p.His157Tyr) variant in the TREM2 gene [45]. Additionally, the c.140G>A (p.Arg47His) variant in the TREM2 gene, associated with European ancestry, was found in both homozygous and heterozygous carriers [45]. These findings reinforce the significant role of genetic admixture in shaping the prevalence of inherited disorders.

In conclusion, we find evidence of both consanguinity-linked founder effect mutations, with Spanish ancestral origins, and admixture-generated compound heterozygotes, with hybrid Spanish, Native American, and Sephardic Jewish ancestral origins, among the Colombian OCA patients studied here. These results highlight the complex genetic architecture of autosomal recessive diseases in admixed American populations and underscore the kinds of insights that can be gained by studying disease genetics in ancestrally diverse populations.

Acknowledgments

The authors wish to thank all the members of the OCA-affected families who took part in the study. They also wish to thank the Departamento Administrativo de Ciencia, Tecnología e Innovación–Colciencias (Call 617–2013) and the Fondo de Apoyo a Doctorados de la Universidad de los Andes (2017) for their support of Wilmer Cardenas’s PhD program, as well as Fundación Ceiba for funding Diana Núñez’s doctoral studies.

Data Availability

All relevant data are within the manuscript.

Funding Statement

This work was supported by the Facultad de Ciencias at Universidad de los Andes through the 2018-1 Research Project Funding Call and the 2023 Call (INV-2023-162-2849) (awarded to MCL). Additional funding was provided by the Georgia Institute of Technology (RF383) (awarded to KIJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0313777.r001

Decision Letter 0

Arnar Palsson

20 Mar 2024

PONE-D-23-39938Ancestral origins of TYR and OCA2 gene mutations in Oculocutaneous albinism from two admixed populations in ColombiaPLOS ONE

Dear Dr. Nunez-Rios,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

The study represents a small but curious study of genes influencing a Mendelian trait in admixed human populations. We had a hard time securing reviewers and the editor eventually took on the role of reviewing. We apologize for the delay. The work is of sufficient quality for PLOS one, but the MS lacks some polishing of narrative and the writing itself.

See the very excellent points by the reviewer, and the following from the editor.

The three major points are

The results section lacks context and focus. Specifically, the second paragraph (Line 119.) dives straight to specifics and plenty of un-defined abberviations are used (IBS, NAM). Restructure this part, open with a general results statement that captures the details the follow. “First we analyzed a familial case, and then studied unrelated individuals…” Use the structure. We wanted to know … To addrss that we did … The data revealed … (rephrase as needed). See also minor points below
The population genetic methods are lacking in detail. Starting Line 248. This includes how many samples analyzed? How many SNPs on this chip? How many polymorphic in your sample? How many markers / invidividuals were used in each analyses? Same dataset in all or subsets in some? Which version of MEGA? How wide a region around OCA/TYR?
The language needs considerable work. See numerous smaller pointers from the editor below, but you are strongly encouraged to scrutinize the manuscript for English grammar errors because many must have eluded me. Getting a 3^rd party or native english friend to read may help.

==============================

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Arnar Palsson, Ph.D.

Academic Editor

PLOS ONE

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Additional Editor Comments:

See the very excellent points by the reviewer, and the following from the editor.

The three major points are

1. The results section lacks context and focus. Specifically, the second paragraph (Line 119.) dives straight to specifics and plenty of un-defined abberviations are used (IBS, NAM). Restructure this part, open with a general results statement that captures the details the follow. “First we analyzed a familial case, and then studied unrelated individuals…” Use the structure. We wanted to know … To addrss that we did … The data revealed … (rephrase as needed). See also minor points below

2. The population genetic methods are lacking in detail. Starting Line 248. This includes how many samples analyzed? How many SNPs on this chip? How many polymorphic in your sample? How many markers / invidividuals were used in each analyses? Same dataset in all or subsets in some? Which version of MEGA? How wide a region around OCA/TYR?

3. The language needs considerable work. See numerous smaller pointers from the editor below, but you are strongly encouraged to scrutinize the manuscript for English grammar errors because many must have eluded me. Getting a 3rd party or native english friend to read may help.

Minor comments.

Italicize gene names in text.

Line 26.

Does prior knowledge lead to this conclusion “patients from two regions of Colombia that show distinct patterns of genetic ancestry“? Or is this a finding from this study? Could “with“ work instead?

Line 29

OCA1 (and OCA2 below) show up as undefined abbreviations. Are the trait subtypes are do they refer to the genetics?

Line 36.

Reword “region have homozygous… of spanish”

Line 46.

Not right choice of words “On the contrary,” In contrast??

Line 49

Drop “of receiving”

Line 56.

Reword “goal” is not the right term her.

Line 60

Reword sentence. “underserved” is not the right word here

Line 64

First statement is categorically wrong. Genetic disorders can be studied on other continents just fine in absence of this history. Open with something more general.

Line 71

Why roman numbers and referring to centuries? Use regular decades per century please.

Line 79.

Why a special interest in this region? Provide justificaiton, can be pragmatic.

Line 85

No need to say “In Colombia,”, that is pretty clear at this point.

Line 87

Can shorten, drop “both regions are shown in” and just retain “(Figure 1A)”

Line 94

Refer to numbers behind high numbers of “individuals with OCA2”.

Line 98

Reword entire sentence “In this regard, the” Could start with “for example…”

Line 100

Drop “One year later,”

Line 105

Reword the opening sentence of this paragraph. If you want a preamble, refer to the important part of genetics that needs resolving, before stating your aim (and then the local/genetic details of the study system). Also state the specific research questions more clearly. “We asked if/whether ….”

Line 112

Add “can” after outbreeding.

Line 115

Explain better the geography or separation of the two populations studied, that is relevant for this study! The opening as stands does not work. Maybe “we studied OCA in populations from two regions are in the Columbian Andes “ (highlight differences between regions??)

Line 116.

From what data were these graphs generated? What do the graphs show the reader? Subgroups and level of mixing in these two regions??? Cite sources of these data if not newly generated for this study.

Line 132

Reword “With regards to the A787T mutation in the OCA2 gene in Marinilla and Santuario, they all have the same IBS haplotype” perhaps, “All the carriers of the … have the same IBS…”

Also highlight that here you swithc to antoher gene, after all the prior section focusing on TYR.

Line 134.

Explain how these haplotypes were derived/estimated. Add details into the sections above. Am not sure “Suggested” is the best term for the table legend. Name or region alti… lowercase in table. Last column, change to Phenotype (albinism) and recode as Complete, None/absent (without doesn’t work).

Line 138

Reword sentence “using…distance …” Perhaps just “Distances from … revealed”

And “from our samples with the Jews” is arkane wording. Fix. What is the point of this sentence?

Line 145

“is strikingly evident in genetic studies,” Add a citation to back up this statement.

Line 149.

“but also indicates how these phenomena influence in the development of autosomal recessive conditions” Really, am not sure the data show this!

Line 151

“departments”?? regions/ provinces??

Line 157

“magnificent” is not needed. This is not literture.

Line 164.

Reword. “Geographic divergence can result in regional isolation, influences assortative” This sentence talks about geographic separation can lead to divergence, but “geographic divergence” is not a good term.

Line 166.

Again, drop the romans.

Line 167

“matings” instead of “mattings”

Line 170

Move citation up in the sentence (0.0040) and reword this last part. “shown by the A787T homozygous mutation in the OCA2 gene” Maybe “And the homoz… may reflect this level of inbreeding.

Line 173

Not exactly true, two and distinct concepts “Inbreeding is often referred as consanguinity” Reword. Or, is this part needed??

Line 175

“is characteristic” maybe “follows”?

Line 178

Plural “populations”

Line 181 and 183

Bad wording, sentence starts and ends with same wording. And in any rewrite, drop “phenomena”

Line 184

Don’t use “on the contrary”

Line 184.

State the main finding in clear terms at the beginning, before going into specifics.

Line 185.

Reword, some connecting words missing “is the largest city harboring individuals”

Line 190

Reword. Have no idea what “may be increase product of the breeding of distant populations as occur in admixed populations” means.

Line 200.

Reword sentence “effect in this high admixed region.” And should this not also affect other genetic variatns causing recessive diseses?

Line 201

Drop “to report potential effects of inbreeding and outbreeding in the admixed Andean region of Colombia”

Line 208.

Italic de novo

Line 224

Not good wording “with the Native American Human.” What is the acceptable wording in Columbia when referring to the aboriginies in the region?? Perhaps you want to do better, and acknowledge the hardship they have suffered at and since the colonization?

Line 231

“For the present study samples were accessed in March 2017.” What does this mean? Accessed from what?

Line 232.

“Ethical considerations were strictly observed, and” this has to be fleshed out, also in the ethics section. With reference to licences/permits for study.

Line 238

Plural “are homozygotes”

Line 238

Reword, something like

“The pedigree (Figure 2) was modifed, relative to earlier account of …”

Line 351

Which data used in this figure were newly generated for this study? What do the Columbian sub groups indicate (OCA and Antio…).

Line 367

Is this pedigree showing TWO genes? The coding of TYR and OCA is confusing.

According to legend “TYR haplotypes are shown as white, whereas mutated OCA haplotypes are color coded“ Im quite confused.

Explain in legend which gene does the variants status G47D refer to?

Figure 3.

Green and red colours are not friendly for the genetic carriers of colour blind genes. Please change colour palette.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Ancestral origins of TYR and OCA2 gene mutations in Oculocutaneous albinism 2 from two admixed populations in Colombia.

The manuscript needs to be proof read with careful consideration to English language, grammar and sentence construction.

Introduction –

1. The Research study looks at the ancestral origins of 2 genes, mutations in which play an important role in manifestation of Oculocutaneous Albinism 2 (OCA2) in two admixed populations of Columbia.

2. The historical context about the region helps the reader understand the history of this region.

3. It is unclear from the present text as to why authors are interested in investigating mutations of TYR, and OCA2 genes. The research question needs to be better outlined. Elaborating this will explain the need to look at ancestral origins of OCA mutations.

4. This study builds on previous research done by the team, however inclusion of this data (in form of tables) needs to be incorporated and background work needs to be elaborated to build connections to present study (Page 5; 85-94; 106).

5. What are inbreeding estimates of the study populations? Authors should provide relevant data to support the statement that “By examining population migration in the Andes regions and ancestral origins of the described mutations we report how both inbreeding and outbreeding increase the risk to develop autosomal recessive traits.” (Page 6; 111-113)

Results –

6. Page 6; 116-118 – PCA analysis and global ancestry analysis should be explained for study populations.

7. The methods focus on haplotype comparisons using pedigree. The choice and justification of this methodological approach should be highlighted.

8. Results to be sectioned based on analysis. Detailed results to be explained for the pedigree and transmission of OCA mutations.

9. Role of inbreeding is not measured nor indicated in results as stated in Introduction

Discussion –

10. Page 8; 147-150 - This study is not investigating the complex demographic history of region but is trying to infer patterns of 2 gene mutations in the context of the complex demographic history of Columbia.

11. A large part of the discussion focuses on history and ancestry of these populations and region. While this is essential, authors should focus on genes under study and discuss their results in context of prior work and population history of the region.

12. Page 10; 181-183 – is there evidence of homozygosity due to inbreeding for other loci from this region to support this statement?

13. Page 10; 184-186 – Authors should provide reference of estimates of genetic diversity of Bogotá, the capital of Colombia.

14. Author’s proposal that compound heterozygotes found in individuals who carry mutations derived from varied ancestral sources can be due to outbreeding needs support from other population genetics studies. It may be useful to use population genetic models to explain how inbreeding and outbreeding affect compound heterozygotes.

Methodology –

15. Samples size is too limited to perform robust statistical analysis.

16. Methodological choice of taking pedigree data needs to be justified.

17. Authors should include a brief description of study participants and their recruitment here for clarity and not just cite the previous study.

18. How was the recruitment done for non-related individuals and what were ethical considerations while recruiting them.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Manjari Jonnalagadda, PhD

**********

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PLoS One. 2024 Nov 18;19(11):e0313777. doi: 10.1371/journal.pone.0313777.r002

Author response to Decision Letter 0

24 Jun 2024

Editor comments and author responses

Editor summary. The study represents a small but curious study of genes influencing a Mendelian trait in admixed human populations. We had a hard time securing reviewers and the editor eventually took on the role of reviewing. We apologize for the delay. The work is of sufficient quality for PLOS one, but the MS lacks some polishing of narrative and the writing itself.

Author response to editor summary. We were pleased to read that editor and reviewer found our manuscript to be of interest and worthy of publication in PLOS ONE pending substantial improvements in the writing and narrative. We are particularly grateful that the editor took on the role of reviewing given the difficulty in securing reviewers. We had one of the native English-speaking coauthors (IKJ) completely rewrite the manuscript to improve the writing, focus, and narrative arc. We detail the changes made in response to the editor and reviewer comments below, indicating how and where we changed the manuscript in response to each point.

See the very excellent points by the reviewer, and the following from the editor.

The three major points are

Editor comment # 1. The results section lacks context and focus. Specifically, the second paragraph (Line 119.) dives straight to specifics and plenty of un-defined abberviations are used (IBS, NAM). Restructure this part, open with a general results statement that captures the details the follow. “First we analyzed a familial case, and then studied unrelated individuals…” Use the structure. We wanted to know … To address that we did … The data revealed … (rephrase as needed). See also minor points below

Author response to editor comment #1. We have revised the entire Results section as suggested to improve context and focus. We are sure to define all abbreviations when they first appear in the manuscript, but we have largely tried to avoid unnecessary abbreviations throughout (eg see revised Table 1). We appreciate the suggestions for how to structure this part, and we have tried to follow them throughout (see revised Results section).

Editor comment #2. The population genetic methods are lacking in detail. Starting Line 248. This includes how many samples analyzed? How many SNPs on this chip? How many polymorphic in your sample? How many markers / invidividuals were used in each analyses? Same dataset in all or subsets in some? Which version of MEGA? How wide a region around OCA/TYR?

Author response to editor comment #2. We have revised the entire Methods section as suggested to provide all of the key missing details as prompted by the editor (see revised Methods section with new subsections on Genetic variant analysis and Genetic ancestry inference).

Editor comment #3. The language needs considerable work. See numerous smaller pointers from the editor below, but you are strongly encouraged to scrutinize the manuscript for English grammar errors because many must have eluded me. Getting a 3rd party or native english friend to read may help.

Author response to editor comment #3. We are very grateful that the editor took the time and effort to provide so many suggestions for how to improve the grammar. As suggested, we had one of the native English-speaking coauthors completely rewrite the manuscript to improve the writing, focus, and narrative arc. Please note that instead of trying to improve the wording by addressing each of the editor’s very helpful grammar suggestions directly, we revised the entire manuscript. (Thus, we do not provide point-by-point responses to those comments).

Reviewer #1 comments and author responses

Reviewer #1 summary. Ancestral origins of TYR and OCA2 gene mutations in Oculocutaneous albinism 2 from two admixed populations in Colombia. The manuscript needs to be proof read with careful consideration to English language, grammar and sentence construction.

Author response to editor summary. As suggested by the reviewer and editor, we had one of the native English-speaking coauthors completely rewrite the manuscript with careful consideration to the English language, grammar, and sentence construction. We greatly appreciate the comprehensive and thoughtful comments provided by the reviewer. We have addressed all of the reviewer’s comments and revised our manuscript accordingly. Below, we indicated how and where we revised the manuscript in response to each comment.

Introduction

Reviewer #1 comment #1. The Research study looks at the ancestral origins of 2 genes, mutations in which play an important role in manifestation of Oculocutaneous Albinism 2 (OCA2) in two admixed populations of Columbia.

Reviewer #1 comment #2. The historical context about the region helps the reader understand the history of this region.

Author response to reviewer #1 comments #1-2. We are glad that the reviewer found our study on the genetics of Albinism in two admixed populations of Colombia to be of interest and appreciate the recognition that the historical context is helpful to the readers.

Reviewer #1 comment #3. It is unclear from the present text as to why authors are interested in investigating mutations of TYR, and OCA2 genes. The research question needs to be better outlined. Elaborating this will explain the need to look at ancestral origins of OCA mutations.

Author response to reviewer #1 comment #3. We have completely re-written the Introduction and Discussion to provide better context on why we are investigating mutations of TYR and OCA2 genes. As suggested, we have clearly specific our hypothesis and research objective in the revised manuscript.

Reviewer #1 comment #4. This study builds on previous research done by the team, however inclusion of this data (in form of tables) needs to be incorporated and background work needs to be elaborated to build connections to present study (Page 5; 85-94; 106).

Author response to reviewer #1 comment #4. As suggested, we have worked to clarify how the findings of our previous work on the genetics of OCA, and the work of others in the field, informs the current study. In particular, we clarify that OCA-causing mutations were characterized in previous studies, whereas we are inferring the ancestral origins of the haplotypes on which these mutations reside for our current study (see revised Introduction and Table 1 for mutations characterize from previous work together with ancestry inferences from this study).

Reviewer #1 comment #5. What are inbreeding estimates of the study populations? Authors should provide relevant data to support the statement that “By examining population migration in the Andes regions and ancestral origins of the described mutations we report how both inbreeding and outbreeding increase the risk to develop autosomal recessive traits.” (Page 6; 111-113)

Author response to reviewer #1 comment #5. We have simultaneously tried to tone down the language on inbreeding and outbreeding, while also providing explicit support for any assertions related to these concepts from our own findings (eg Figure 3 and Table 1) and previous studies. We do not discuss inbreeding or outbreeding in the revised Introduction. Rather, we only bring in these concepts in the Discussion as a theoretical framing of our results (see Discussion page 11 paragraph 3). We do provide a citation to a previous study on inbreeding coefficient in the Marinilla-Santuario region, but we also mention here that “However, given the relatively low sample size of two Marinilla-Santuario samples, and the lack of pedigree linking these samples, this conclusion is not as well supported as the G47D founder mutation.” (see Discussion, page 12, paragraph 2).

Results

Reviewer #1 comment #6. Page 6; 116-118 – PCA analysis and global ancestry analysis should be explained for study populations.

Author response to reviewer #1 comment #6. As suggested, we provide additional details on PCA in the Methods section on Genetic ancestry inference (see Methods, page 6, first paragraph) and the Results section on Genetic ancestry and admixture of Colombian OCA patients (see Results, page 6, second paragraph).

Reviewer #1 comment #7. The methods focus on haplotype comparisons using pedigree. The choice and justification of this methodological approach should be highlighted.

Author response to reviewer #1 comment #7. We have rewritten the Introduction, Methods, and Results sections to clarify that we use haplotype analysis in order to infer the ancestral origins of TYR and OCA2 mutations.

Reviewer #1 comment #8. Results to be sectioned based on analysis. Detailed results to be explained for the pedigree and transmission of OCA mutations.

Author response to reviewer #1 comment #8. As suggested, in the revised manuscript we clarify exactly what the pedigree allows us to observe, ie the inheritance patterns on TYR mutations together with their ancestral origins in the Results (see page 10, first paragraph) and in the Discussion (see page 11, third paragraph and page 12, third paragraph).

Reviewer #1 comment #9. Role of inbreeding is not measured nor indicated in results as stated in Introduction

Author response to reviewer #1 comment #9. We have simultaneously tried to tone down the language on inbreeding and outbreeding, while also providing explicit support for any assertions related to these concepts from our own findings (eg Figure 3 and Table 1) and previous studies. We do not discuss inbreeding or outbreeding in the revised Introduction. Rather, we only bring in these concepts in the Discussion as a theoretical framing of our results (see Discussion page 11 paragraph 3). We do provide a citation to a previous study on inbreeding coefficient in the Marinilla-Santuario region, but we also mention here that “However, given the relatively low sample size of two Marinilla-Santuario samples, and the lack of pedigree linking these samples, this conclusion is not as well supported as the G47D founder mutation.” (see Discussion, page 12, paragraph 2).

Discussion

Reviewer #1 comment #10. Page 8; 147-150 - This study is not investigating the complex demographic history of region but is trying to infer patterns of 2 gene mutations in the context of the complex demographic history of Columbia.

Author response to reviewer #1 comment #10. We agree. We have removed this statement and completely rewritten the Discussion to focus on what we actually did in the paper, ie analyze the ancestral origins of TYR and OCA2 mutations.

Reviewer #1 comment #11. A large part of the discussion focuses on history and ancestry of these populations and region. While this is essential, authors should focus on genes under study and discuss their results in context of prior work and population history of the region.

Author response to reviewer #1 comment #11. We agree. We have removed much of this unnecessary material from the revised Discussion, which now focuses on the genes under study and the ancestral origins of the mutations in the context of prior work and the population history of the region.

Reviewer #1 comment #12. Page 10; 181-183 – is there evidence of homozygosity due to inbreeding for other loci from this region to support this statement?

Author response to reviewer #1 comment #12. We do have evidence from the phylogeny in Figure 2 and the pedigree shown in Figure 3 that the same haplotype was inherited from both parents for two affected individuals, pointing to some degree of consanguinity. Nevertheless, as stated in response to other comments on this same point we have simultaneously tried to tone down the language on inbreeding and outbreeding, while also providing explicit support for any assertions related to these concepts from our own findings (eg Figure 3 and Table 1) and previous studies. We do not discuss inbreeding or outbreeding in the revised Introduction. Rather, we only bring in these concepts in the Discussion as a theoretical framing of our results (see Discussion page 11 paragraph 3). We do provide a citation to a previous study on inbreeding coefficient in the Marinilla-Santuario region, but we also mention here that “However, given the relatively low sample size of two Marinilla-Santuario samples, and the lack of pedigree linking these samples, this conclusion is not as well supported as the G47D founder mutation.” (see Discussion, page 12, paragraph 2).

Reviewer #1 comment #13. Page 10; 184-186 – Authors should provide reference of estimates of genetic diversity of Bogotá, the capital of Colombia.

Author response to reviewer #1 comment #13. We have eliminated any unsupported statements on genetic diversity as suggested. Please see our response to the above comment #12 as well.

Reviewer #1 comment #14. Author’s proposal that compound heterozygotes found in individuals who carry mutations derived from varied ancestral sources can be due to outbreeding needs support from other population genetics studies. It may be useful to use population genetic models to explain how inbreeding and outbreeding affect compound heterozygotes.

Author response to reviewer #1 comment #14. On the one hand, our revised manuscript now shows clear evidence of admixture-derived compound heterozygotes, and we hope that this now comes across much more clearly. On the other hand, as stated in response to previous comments, we have completely rewritten the Introduction and Discussion to tone down the discussion of inbreeding and outbreeding. We only mention this now in the Discussion where we have explicit support from our own results and we tie this directly to previous theoretical literature on the subject (see Discussion page 11 paragraph 3, and page 12 paragraphs 2 & 3).

Methodology

Reviewer #1 comment #15. Samples size is too limited to perform robust statistical analysis.

Author response to reviewer #1 comment #15. In our revised manuscript, we now clarify that our study aims to provide a descriptive analysis of the ancestral origins of the TRY and OCA2 mutations. Despite the low sample size of our study cohort, the large amount of genome-wide variant data that we characterized (~720k variants) and the large number of global reference samples that we used (515) provide sufficient resolution for us to achieve this objective. New details on these numbers can be found in the revised Methods section on Genetic ancestry inference (see page 6, paragraph 1).

Reviewer #1 comment #16. Methodological choice of taking pedigree data needs to be justified.

Author response to reviewer #1 comment #16. In the revised manuscript, we more clearly illustrate the utility of the pedigree to simultaneously illustrate the inheritance patterns of TYR mutations in a Colombian family and their ancestral origins (see Results, page 10, paragraph 1; Discussion, page 11, paragraph 3 and page 12, paragraph 3).

Reviewer #1 comment #17. Authors should include a brief description of study participants and their recruitment here for clarity and not just cite the previous study.

Author response to reviewer #1 comment #17. As suggested, we provide additional details on study participants and their recruitment in the revised Methods section on Study cohort and ethics (see page 4, paragraph 3 to page 5, paragraph 1)

Reviewer #1 comment #18. How was the recruitment done for non-related individuals and what were ethical considerations while recruiting them.

Author response to reviewer #1 comment #18. As suggested, we provide additional details on participant recruitment and all ethical considerations in the revised Methods section on Study cohort and ethics (see page 4, paragraph 3 to page 5, paragraph 1)

Attachment

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PLoS One. doi: 10.1371/journal.pone.0313777.r003

Decision Letter 1

Arnar Palsson

5 Jul 2024

PONE-D-23-39938R1Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in ColombiaPLOS ONE

Dear Dr. Nunez-Rios,

==============================

Adhere to the points made by reviewer 1.

In particular the restructuring of the discussion.

Author response to Decision Letter 1

21 Aug 2024

Manuscript Title: Ancestral origins of TYR and OCA2 gene mutations in Oculocutaneous albinism 2 from two admixed populations in Colombia

Dear Editor and reviewers, we are particularly grateful for your valuable comments. We detail the changes made in response to the editor and reviewer comments below, indicating how and where we changed the manuscript in response to each point.

Introduction –

1. “We are interested in the relationship between genetic ancestry, admixture, and the presence of mutations that cause oculocutaneous albinism (OCA) in Colombian populations from the Andean region.” – Why? can authors state why this trait (and thereby genes OCA2 and TYR) is of interest to them? Is there a phenotypic association of significance in this population?

Response: We have added information to the abstract, introduction, and discussion to clarify our interest in this trait. Specifically, we explained that this study builds on our previous findings, aiming to explore the ancestral origins of reported mutations in the context of Colombia's complex colonization history. Understanding these origins is critical for deciphering the genetic basis of OCA in this region, where unique admixture patterns may influence disease prevalence.

2. The specific objective of this study was to test our admixture-derived compound

heterozygote hypothesis by characterizing the ancestral origins of TYR mutations from Altiplano Cundiboyacense and OCA2 mutations from the Marinilla-Santuario region in Antioquia” - The proposed hypothesis - admixture-derived compound heterozygote hypothesis has support from a previous study looking at the G47D mutation in OCA patients living in the Canary Islands and Puerto Rico and suggested to have Sephardic Jewish origin based on its high prevalence among Moroccan Jews living in Israel [23]. If the authors are retesting this hypothesis in the Andean population, they need to explain the changed/varied context that demands retesting of the hypothesis. It could be as simple as effect of these heterozygote mutations on this population.

Response: We have expanded our explanation to clarify that the origins of mutations found in OCA patients from Colombia remain uncertain. Considering the multiple waves of immigration and complex admixture in Colombia, along with diversity in genetic backgrounds that can lead to unique combinations of mutations that might not be observed in more genetically homogeneous populations, we aimed to examine the ancestral origins of these mutations and then correlate those findings with inbreeding and outbreeding depression in the examined regions.

3. “We characterized the genome-wide patterns of genetic ancestry for OCA patients from Altiplano Cundiboyacense and Antioquia, confirming European and Native American admixture with little African ancestry.. Our results underscore the genetic complexity of Mendelian disease in admixed Latin American populations” – this is a part of this study? The placement of the paragraph is odd as part of the introduction. It is suggested to include this section as part of the introduction to the discussion.

Response: We have removed the mentioned paragraph from the introduction and integrated the relevant information into the results and discussion sections

Results

– “The OCA1 patients studied here were sampled from in …. or near Altiplano Cundiboyacense, primarily in the departments of Cundinamarca and Boyacá (Figure 1A) …. genomic variant data from African, European, and Native American reference populations.” – This content is repeated. It’s already included in Methods Study cohort section.

Response: This information has been removed from the results section and was appropriately integrated to avoid redundancy.

4. “Principal component analysis (PCA) shows that the Colombian OCA patients studied here group closely together and fall between the… principal component 2

(PC2; Figure 1B) - statement can be changed to PCA was performed to evaluate… and PCA shows ….

Response: We have revised this section to reflect the suggestion. The methods paragraph describing the PCA was removed, and the results were rephrased to clarify that PCA was performed to evaluate genetic clustering, and the results were described accordingly.

5. “The pedigree in Figure 3 shows the inheritance patterns and ancestral origins for OCA1 causing

TYR mutations…. – Firstly, acquisition of Pedigree data (why, how) doesn’t find any mention in the methods section. Pedigree data is crucial to testing the admixture-derived compound heterozygote hypothesis, it must be included in the Methods section.

Response: We have added a detailed explanation of the acquisition and analysis of pedigree data in the Methods section, highlighting that this study builds on our previous findings from our group and the same nomenclature is preserved here.

Authors can consider the following points to revise the discussion.

1. The discussion can begin with “Our study on the genetic etiology of OCA in Colombia highlights the valuable insights that can be obtained from clinical genomics studies of Latin American populations characterized by significant genetic admixture…..Andean region, where our study populations live, is characterized by two-way European and Native American ancestry, including a previously hidden Converso ancestry component (Figure 1) [12].”

Response: The discussion has been rewritten to follow a more logical flow, beginning with a broader overview of our study's significance in the context of genetic studies of Latin American populations, then moving to specific findings from our study.

2. Why the focus on OCA?

Response: This suggestion has been incorporated along the manuscript

3. Summarize the key findings here and explain their patterns in context of admixture and ancestry of study populations and highlight ancestry profile of Columbians in general. Highlight previous studies on genetic etiology of OCA in Colombia characterized by significant genetic admixture and OCA (OCA1 and OCA2) frequencies in Columbian populations if any. If not, states there aren’t any other studies investigating this.

Response: We have expanded the discussion to include a summary of key findings, contextualizing them within the broader ancestry profile of Colombians. We also highlighted the significance of our previous studies and noted the lack of comprehensive data on OCA frequencies in Colombian populations, underscoring the importance of this research.

4. Explain Pedigree data and draw parallels with other diseases studied in these populations.

Response: We added a comparison to other studies conducted in the same regions, reinforcing the idea that the genetic complexity resulting from admixture increases the likelihood of inherited disorders due to compound heterozygosity.

Attachment

Submitted filename: OCA_Admixed_Populations-ResponsestoReviewers.docx

pone.0313777.s004.docx^{(24.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0313777.r005

Decision Letter 2

Arnar Palsson

10 Oct 2024

PONE-D-23-39938R2Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in ColombiaPLOS ONE

Dear Dr. Nunez-Rios,

The reviewers gave the green light on the manuscript but I found a few minor things that I want you to fix before acceptance.

Comment

First off, it is not helpful that the manuscript did not come with line numbers, that the “track changes“ version was nearly all read that there was a third version of the manucript in the submission package. Please proved a better “track changes“ version for the final submission.

Figure 1B is unclear as some individuals sit on top of one another in the PC plot. Redo the figure either with smaller symbols or some level of transparency.

Figure 2 legend (and maybe result text). How long are the regions used to determine the haplotype ancestry around TYR? The genomic region in kb and perhaps also the nr of SNP used to define their ancestry.

The verb “characterize“ is used liberally. Below I suggest some place where it can be dropped. Please skim through and check other places where simpler verbs may suffice.

Minor comments.

==============================

Please submit your revised manuscript by Nov 24 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Arnar Palsson, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

The reviewers gave the green light on the manuscript but I found a few minor things that I want you to fix before acceptance.

Comment

Figure 1B is unclear as some individuals sit on top of one another in the PC plot. Redo the figure either with smaller symbols or some level of transparency.

The verb “characterize“ is used liberally. Below I suggest some place where it can be dropped. Please skim through and check other places where simpler verbs may suffice.

Minor comments.

Page 4 line 5-

Replace“ may have introduced OCA causing mutations with distinct

ancestral origins onto the same genetic background in individuals from the Andean region” with “may have lead to multiple OCA mutations of distinct ancesries segregating in individuals in the Andean region”

Page 4 line 7.

Provide a citation for the “admixture-derived compound heterozygote hypothesis” from the literature.

Page 4, paragraph 3

Replace “Our findings demonstrate that the G47D mutation is present on a Spanish-origin haplotype and not a Sephardic Jewish” with

“The data demonstrate that the G47D mutation sits on on a Spanish-origin haplotype and not a Sephardic Jewish…”

Page 5, paragraph 3

Replace “as described for the previous studies where these samples were first reported [21, 22]” with “as described in previous studies on these individuals [21, 22]”

Page 5, paragraph 4

Replace “The same samples were characterized for this study with” with “These individuals were genotyped with”

Page 5, paragraph 4, line 8

Remove “taken”

Page 6, line 1.

Reword “local (i.e. haplotype-specific) ancestry inference”

To “local (i.e. haplotype around the TYR and OCA genes) ancestry inference”

Page 11, paragraph 2, line 2

Replace “Latin American populations characterized by significant genetic” to “Latin American populations with significant genetic”

Page 11, paragraph 2, line 5

Replace “The Colombian population is characterized by African, European” to “The Colombian population has African, European”

Page 11, paragraph 2, line 8.

Reword “The Andean region, where our study populations live, is characterized by two-way…” to “The study population in the Andean region mainly has European and Native American ancestry, and as the data revealed a notable Converso ancestry component”

Page 11, paragraph 3, line 4

Reword “are homozygous with copies of the same G47D haplotype” to

“are homozygous for the same G47D haplotype”

Page 12, paragraph 2, line 3

Reword “A previous study found that the Marinilla-Santuario region had the highest inbreeding coefficient in Colombia [42], consistent with the idea that the A787T mutation also

represents a founder effect.” To “This observation and the previous finding that the Marinilla-Santuario region had the highest inbreeding coefficient in Colombia [42], is consistent with the idea that a founder event influenced variation in this region in particular”

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: Authors have addressed the concerns raised and provided necessary changes to make the manuscript a better read.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Manjari Jonnalagadda

**********

PLoS One. 2024 Nov 18;19(11):e0313777. doi: 10.1371/journal.pone.0313777.r006

Author response to Decision Letter 2

29 Oct 2024

We appreciate the reviewers' insightful comments and suggestions, which have been invaluable in refining our manuscript. In response, we have carefully addressed each point and made corresponding changes, as outlined in detail below

1. First off, it is not helpful that the manuscript did not come with line numbers, that the “track changes“ version was nearly all read that there was a third version of the manuscript in the submission package. Please proved a better “track changes“ version for the final submission.

Changes made to the manuscript were implemented as follows:

a) In the first round of corrections, the manuscript was revised by a native English speaker. All edited paragraphs are marked in red.

b) In the second round of corrections, track changes were used to document revisions.

c) In the third round of corrections, track changes were again utilized, with all modifications highlighted in yellow.

2. Figure 1B is unclear as some individuals sit on top of one another in the PC plot. Redo the figure either with smaller symbols or some level of transparency.

Figure 1B was corrected with some level of transparency.

3. Figure 2 legend (and maybe result text). How long are the regions used to determine the haplotype ancestry around TYR? The genomic region in kb and perhaps also the nr of SNP used to define their ancestry.

Information was added in methods text.

4. The verb “characterize“ is used liberally. Below I suggest some place where it can be dropped. Please skim through and check other places where simpler verbs may suffice.

We thank you the reviewers for those suggestions. All changes were highlighted in yellow

Minor comments.

a. Page 4 line 5-

Replace“ may have introduced OCA causing mutations with distinct

Completed

b. Page 4 line 7.

Provide a citation for the “admixture-derived compound heterozygote hypothesis” from the literature.

Citations were added

c. Page 4, paragraph 3

Replace “Our findings demonstrate that the G47D mutation is present on a Spanish-origin haplotype and not a Sephardic Jewish” with

“The data demonstrate that the G47D mutation sits on on a Spanish-origin haplotype and not a Sephardic Jewish…”

This sentence was removed in the second round of corrections. No additional changes were conducted in this round.

d. Page 5, paragraph 3

Replace “as described for the previous studies where these samples were first reported [21, 22]” with “as described in previous studies on these individuals [21, 22]”

Completed

e. Page 5, paragraph 4

Replace “The same samples were characterized for this study with” with “These individuals were genotyped with”

Completed

f. Page 5, paragraph 4, line 8 Remove “taken”

Completed

g. Page 6, line 1.

Reword “local (i.e. haplotype-specific) ancestry inference”

To “local (i.e. haplotype around the TYR and OCA genes) ancestry inference”

Completed

h. Page 11, paragraph 2, line 2

Replace “Latin American populations characterized by significant genetic” to “Latin American populations with significant genetic”

Completed

i. Page 11, paragraph 2, line 5

Replace “The Colombian population is characterized by African, European” to “The Colombian population has African, European”

Completed

j. Page 11, paragraph 2, line 8.

Completed

k. Page 11, paragraph 3, line 4

Reword “are homozygous with copies of the same G47D haplotype” to

“are homozygous for the same G47D haplotype”

Completed

l. Page 12, paragraph 2, line 3

Reword “A previous study found that the Marinilla-Santuario region had the highest inbreeding coefficient in Colombia [42], consistent with the idea that the A787T mutation also

Completed

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PLoS One. doi: 10.1371/journal.pone.0313777.r007

Decision Letter 3

Arnar Palsson

31 Oct 2024

Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in Colombia

PONE-D-23-39938R3

Dear Dr. Nunez-Rios,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Arnar Palsson, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0313777.r008

Acceptance letter

Arnar Palsson

7 Nov 2024

PONE-D-23-39938R3

PLOS ONE

Dear Dr. Nunez-Rios,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

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PERMALINK

Ancestral origins of TYR and OCA2 gene mutations in oculocutaneous albinism from two admixed populations in Colombia

Wilmer A Cárdenas

Andrew B Conley

Shashwat Deepali Nagar

Diana L Núñez-Ríos

I King Jordan

María Claudia Lattig

Roles

Abstract

Introduction

Fig 1. Genetic ancestry and admixture in Altiplano Cundiboyacense and Marinilla-Santuario.

Methods

Study cohort and ethics

Genetic variant analysis

Genetic ancestry inference

Results

Genetic ancestry and admixture of Colombian OCA patients

Ancestral origins of TYR and OCA2 mutations

Fig 2. Ancestry inference for the oculocutaneous albinism (OCA) causing TYR gene haplotypes G47D and 1379delTT.

Table 1. TYR and OCA2 mutations and haplotype origins.

Fig 3. Origin of oculocutaneous albinism (OCA) causing TYR gene haplotypes in a Colombian family.

Discussion

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Arnar Palsson

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Author response to Decision Letter 0

Decision Letter 1

Arnar Palsson

Roles

Author response to Decision Letter 1

Decision Letter 2

Arnar Palsson

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Author response to Decision Letter 2

Decision Letter 3

Arnar Palsson

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Acceptance letter

Arnar Palsson

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Associated Data

Supplementary Materials

Data Availability Statement

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