Which field of research would Gregor Mendel choose in the 21st century?

Abstract

Gregor Mendel’s work on segregation of traits in plants established the basic methodology and rules of genetics. The interruption of Mendel’s research activities in 1870 impeded the immediate recognition of the value of his work until the dawn of the 20th century. Only then were his founding laws of genetics validated, propelling the development of biological research toward the birth of molecular biology in the second half of the 20th century. While molecular plant genetics can be viewed as the spiritual heir of Mendel’s research, one might wonder whether in the 21st century Gregor Mendel would prefer to practice scientific approaches other than molecular genetics such as population genetics, comparative genomics, or the emerging field of evo-chromo. In this perspective, I review aspects of these fields that might have attracted or perplexed a 21st century Mendel.

Beyond the impact of Gregor Mendel’s work on the birth of genetics, the author wonders what type of research Mendel would have chosen in the 21st century.

Introduction

This perspective commemorates the 200th birthday of Gregor Mendel. From a historical perspective, there would appear to be a natural affiliation between Mendel’s work, genetics, and ultimately the field of molecular genetics that has dominated progress in the last three decades. The celebration of Mendel’s birthday by The Plant Cell shows that plant molecular biologists view themselves as the spiritual heirs of Mendel’s experimental approach. The history of plant molecular biology also has deep roots in the development of the experimental approach in life sciences. The end of the 18th and 19th centuries saw the emergence of experimental biology with works by Lazzaro Spallanzani (1729–1799), John Stuart Mill (1806–1873), Charles Darwin (1809–1882), and Louis Pasteur (1822–1895). These pioneers paved the way for experimental manipulations of living systems to study how the phenotype is built from molecular mechanisms. A distinct strategy to investigate the connection between phenotype and genotype was developed in parallel by Jean-Baptiste Lamarck (1744–1829), Alfred Wallace (1823–1913), and Darwin, which framed theories of evolution. These strategies are based solely on observations producing hypotheses that have ever since been tested with increasingly powerful tools like next-generation sequencing, automated phenotyping, and advanced statistics used currently in population genetics and comparative genomics. All of Mendel’s papers were burned by his successor, leaving us with no direct records of his experiments and with gaps in our understanding of his scientific approach. There are very few direct historical sources relating Mendel’s way of thinking (van Dijk et al., 2018) and one may wonder, if Mendel were born in the 21st century would he engage in comparative genomics, population genetics, or molecular genetics?

Historical considerations

More than 150 years have passed since the publication of Mendel’s major work proposing the principles governing the inheritance of traits in 1866 (Mendel, 1866). Although this manuscript was not widely noticed after its publication, several researchers were aware of Mendel’s work. It was mentioned in 1881 by Wilhelm O. Focke and in 1892 and 1895 by LH Bailey (MacRoberts, 1984). Charles Darwin was aware of Focke’s manuscript and passed it to his assistant George Romanes who corresponded with Focke (Forsdyke, 2018). Yet, it was only after 1900 that Mendel’s work became broadly publicized and appreciated. The Swiss botanist Carl Nägeli corresponded actively with Mendel, and Carl Correns, who married C. Nägeli’s niece, published the 10 letters exchanged between Mendel and Nägeli, which provide an important testimony on his experimental method and unpublished work (Correns, 1905; Mendel, 1950; van Dijk and Ellis, 2016). The study on crosses at Tübingen University by Correns in 1896–1899 verified Mendel’s law (Correns, 1900). In parallel, the Dutch botanist Hugo de Vries conducted experiments that led to the same conclusions reached by Mendel 35 years earlier (de Vries, 1899). de Vries (1900) recognized the impact of Mendel’s work only in his second publication on the topic under pressure from Correns (Bateson, 1902). Two other researchers also participated in publicizing Mendel’s laws—the Austrian brothers Armin and Erich von Tschermak-Seysenegg, the grand-sons of Eduard Fenzl who taught botany when Mendel studied in Vienna. The studies of Erich von Tschermak-Seysenegg on hybridization were initiated in Ghent in 1898 following contact with de Vries and led to the publication of the first manuscript written with the full knowledge of Mendel’s papers (Tschermak-Seysenegg, 1900). The correspondence between the two brothers also reveals their complex tangled relationship with de Vries and Correns (Simunek et al., 2011). Independently, after reading de Vries’ second paper in German (de Vries, 1900), Bateson (1902) became aware of Mendel’s work, which he promoted through the translation of the 1866 paper in 1902. This first book was followed by a new book (Bateson, 1913), which included the additional translation of the second paper by Mendel reporting his work on Hieracium (Mendel, 1869). Interestingly, Bateson’s book was translated into German in 1914! Bateson’s impact was important not simply because he translated Mendel’s papers into English (many scientists read in multiple languages at the time) but because his commentary shed new light on Mendel’s work. He grasped the theoretical aspects of Mendel’s work and the importance of statistics in the experimental approach. Bateson also established bridges between the segregation of traits in the progeny of hybrids with the cellular theory of heredity and the work on chromosomes developing during this period. It is interesting to note that the 1902 edition was the development of a lecture to the Royal Horticultural Society in 1899 and took place before the term “genetics” was introduced by Bateson (1908). From that point on, Mendelian laws governing heredity of traits became widely recognized; this was likely essential for the development of genetic models such as drosophila and maize in the first decades of the 20th century.

Molecular genetics

If a 21st century Mendel were interested in identifying the origins of the diverse characteristics that he studied in peas, he would have likely identified the genes and their molecular function—at least for those controlling seed coat color or other aspect of the seeds. Such tasks have become relatively easy with models like Arabidopsis, but still not with all species. To date, molecular work has identified only four of the seven genes related to the seven traits Mendel studied (Reid and Ross, 2011). Even the advanced tools of molecular geneticists do not always define the proximal, direct function of genes. When one manipulates gene activity (loss, gain, and ectopic gain) one observes the manner in which the organism reacts to the change. However, the loss of a gene often has a complex impact on the phenotype and this complexity hinders defining the function of the gene. This constitutes one of the limitations of molecular genetics. A second limiting factor is functional redundancy. These problems have illustrated many times in the field of epigenetics where multiple pathways are involved in the deposition of DNA methylation (Stroud et al., 2013) or transcriptional silencing of transposons (Osakabe et al., 2021). If pea beetles had not destroyed a series of crosses dedicated to measuring flowering time (Mendel’s second letter to Nägeli), Mendel would certainly have followed his original observation that F1 hybrids show intermediate flowering time compared with parental lines (Mendel, 1866). However, we now know the degree of complexity of epigenetic regulation of flowering (Whittaker and Dean, 2017) and this would have perplexed Mendel. One must acknowledge that Mendel had been wisely guided by years of observation of pea varieties from which he chose seven traits which could be appreciated without ambiguity and that are now known to be governed directly by single genes (Mendel, 1866; Bateson, 1902; Reid and Ross, 2011) and he skillfully avoided what we now call non-Mendelian controls (Mittelsten Scheid, 2022).

Mendel’s work focused on the rules that govern the transmission of traits, such as one might use to predict the outcome of a cross between different varieties. He did not show an interest in understanding the mechanisms responsible for the traits he studied. His approach to the natural world was based on observation rather than experimentation, in the sense that he described the segregation of traits that occurred and created models from his observation to reach a conceptual interpretation of the observations. Mendel’s experimental approach was fundamentally descriptive in that his experiments did not disrupt Nature’s laws. The idea of perturbing an experimental system to cause a change in the rules that govern its function might not be appealing to Mendel visiting the 21st century.

Population genetics

The last decade of decoding genomes and genomic analyses has bred new heirs of Mendel, with research strategies that do not seek to perturb the natural system studied but are rather based on deriving knowledge of the mechanisms acting in this system through its exhaustive description. This approach is much closer to the old idea that naming is understanding and that long lists do provide access to Truth. How this idea developed throughout history is fascinating (Ecco, 2009) and modern genomics does tend to acquire knowledge through a reasoned statistical analysis of extensive lists of genomic sequences compiled following various criteria.

Variation-focused quantitative genetics has played a crucial role in understanding selection—with clear impacts on breeding methods in agriculture and crop yield (Hill, 2010). The intense interest in predicting human susceptibility to disease led to the identification of thousands of Mendelian disorders (www.omim.org), which has in turn provided useful genetic predictive markers, and, in some cases, helped to elucidate mechanisms involved in genetic (Boyle et al., 2017; Visscher et al., 2021) and epigenetic controls (Sasaki et al., 2019). Quantitative genetics has improved statistical approaches leading to genomic selection in animal breeding (VanRaden, 2020), and in some cases has resolved the causal link between genotype and phenotype, as in the case of genes that generate coat and skin color in mammals (Beleza et al., 2013) or flower color in plants (Ortiz-Barrientos, 2013). These achievements could have potentially attracted Mendel to engage in population genetics.

Comparative genomics

Another field of research that might attract 21st century Mendel is comparative genomics (Alfoldi and Lindblad-Toh, 2013). By comparing the genomic sequences of diverse organisms, one can understand, at the molecular level, what distinguishes different life forms from each other. This approach provides a powerful tool to identify genes that are conserved or common among species, as well as those genes which confer unique characteristics to different organisms. Recently, this approach led to an understanding of the evolution of symbiosis in land plants (Rich et al., 2021), the evolution of sperm in plants (Higo et al., 2018), and the recurrent but not convergent evolution of crassulacean acid metabolism (Wickell et al., 2021). This strategy also helps outline the general principles of evolution. In metazoans, comparative genomics has revealed how the interplay of mutation, genetic drift, recombination, and retroelement expansion, all shaped by natural selection, results in changes in the transcriptional regulatory landscape. Comparing genomes has also given us clues about the origin of multicellularity in non-bilaterian animals (Sebe-Pedros et al., 2018). The rapid expansion of the repertoire of genome sequences between species and within populations is expected to strengthen the impact of comparative genomics in biological research. Mendel performed crosses using species other than peas and obtained similar results with most other species that he studied (Mendel, 1866; Bateson, 1902; van Dijk and Ellis, 2016). However, over a period of 7 years he observed something different with artificial hybrids of different hawkweeds species (genus Hieracium) (Mendel, 1869). Painstaking crosses of tiny, hand-emasculated flowers led to hybrids that did not segregate parental traits in the F2 progeny. Mendel’s work on Hieracium showed a mode of inheritance distinct from that which he observed in peas and most of the other species he studied. This provided a stimulating basis for further experiments aimed at understanding the causes of these differences. Unfortunately, health problems and his new functions as abbot of St Thomas’s abbey in Brno prevented Mendel from tending to his plants and bees (he had also initiated experiments on crosses between different races of bees). Eventually Mendel sent seeds from crosses to Carl Nägeli, with the hope that these would be passed on for further work. Nothing could be closer to contemporary FAIR data principles (https://www.go-fair.org/fair-principles/)! C. Nägeli grew the hybrids in Munich and several herbaria specimens can still be traced today (van Dijk and Ellis, 2016). It is very likely that, had Mendel been able to carry on with his work, he would have discovered that Hieracium frequently reproduces through apomixis. This process produces seeds that are clones of the mother and explains the absence of trait disjunction in the progenies of interspecific Hieracium hybrids. Apomixis was eventually reported in Hieracium after Mendel’s death using an improved castration method 1903 (Ostenfeld and Raunkiaer, 1903) with subsequent studies describing the impact of apomixis on speciation (Ostenfeld and Rosenberg, 1906). A comparative genomics approach using species of Hieracium recently led to the identification of a gene involved in one of the steps of apomixis (Underwood et al., 2022).

Emerging studies on the role of chromatin in this process (Evo-Chromo) (Drinnenberg et al., 2019) have the objective to understand the evolvability of living systems, another topic that Mendel may have elected if he were to start his research projects today. This field relies of the availability of increasing numbers of genomes assembled as the chromosome levels and improved genomic methods that query the components and organization of the genome with its associated chromatin. Some of these descriptive methods have extended the definition of transcriptional units (Nojima et al., 2015; Lopes et al., 2017) and identified cis-regulatory elements (Marinov and Shipony, 2021) and the stereotypical association of chromatin components into functional chromatin states (Becker et al., 2017). Other methods have identified the specific three-dimensional conformation of the genome within the nucleus (Jerkovic and Cavalli, 2021). Although these methods have been primarily applied to only a few model organisms, they are becoming available for a very large spectrum of organisms with sufficiently well-assembled genomes. These news methods of observation are having a profound impact on our understanding of eukaryotic genome evolution (Drinnenberg et al., 2019; Yocca and Edger, 2021).

Of course, musing through this theme might be futile. The lack of direct documentation on Mendel’s work and the paucity of testimony about his scientific life limit our conception of the long-term scientific objectives of Mendel. Irrespective of who currently claims that they have inherited Mendel’s ways of research, he remains a central figure in the advancement of our conceptual vision of life that has been built throughout the 20th century and as such was certainly half a century ahead of his time.

 

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell) is: Frédéric Berger (frederic.berger@gmi.oeaw.ac.at).