Table 1.
Partial list of genes and genetic elements showing HLS changes
| Gene/Element Name | Mechanism of Change | Proposed Phenotype | Relative Phenotypic Certainty | Possible Gene-Associated Disease | Refs |
|---|---|---|---|---|---|
| Androgen receptor (AR) | Deletion of regulatory DNA/Expression Change | Loss of sensory vibrissae and penile spines | Likely | Androgen insensitivity, hypospadias 1, spinal and bulbar muscular atrophy of Kennedy, prostate cancer susceptibility | 8 |
| Apolipoprotein C-I (APOC1) | Pseudogene | Unknown | N/A | Alzheimer’s severity, atherosclerosis and coronary heart disease | 50–53 |
| Aquaporin 7 (AQP7) | Copy number increase | Energy (glycerol) storage/transport/utilizat ion; increased sweating | Plausible | Nonfunctional glycerol response to exercise | 2, 3, 18, 40, 54–56 |
| Asp (abnormal spindle) homolog, microcephaly associated (ASPM) | Positive selection | Increased Brain Size | Plausible | Microcephaly | 57, 58 |
| CDK5 regulatory subunit associated protein 2 (CDK5RAP2) | Positive selection | Increased Brain Size | Plausible | Microcephaly | 58, 59 |
| Chemokine (C-C motif) ligand 3-like 1 (CCL3L1) | Novel gene variant | Immune function (chemokine for lymphocytes and macrophages) | Likely | HIV/AIDs susceptibility, Kawasaki Disease, Rheumatoid Arthritis, susceptibility to Chronic hepatitis C infection | 56 |
| Cholinergic receptor, muscarinic 3 (CHRM3) | Alternative splicing/Expression change/Novel exon | Change in human reproduction | Plausible | Eagle-Barrett Syndrome | 60 |
| Cholinergic receptor, nicotinic alpha 7 and FAM7A fusion (CHRFAM7A) | Copy number increase | Higher brain function | Plausible | P50 sensory gating deficit | 18, 40, 56, 61 |
| Creatine kinase brain (CKB) | Expression change | Metabolic changes in brain | Plausible | Multiple sclerosis | 4, 62 |
| Cytidine Monophosphate Acetylneuraminic acid hydroxylase (CMAH) | Pseudogene | Changed sialic acid composition on all cells in the body/Secondary effects in multiple systems | Definite | Duchenne muscular dystrophy, Red-meat related carcinoma risk. | 63, 64 |
| Cytochrome c oxidase subunit Va (COX5A) | Amino acid change/Positive Selection | Mitochondrial metabolism | Plausible | 65 | |
| Dopamine receptor D5 (DRD5) | Copy number increase | Regulation of mood, memory, learning, attention, movement | Likely | DRD5 deficiency, ADHD, primary cervical dystonia | 18, 56 |
| DUF1220/Neuroblastoma breakpoint factor (NBPF) family | Protein domain copy number increase (hyperamplification) | Brain size | Likely | Microcephaly, macrocephaly | 18, 23, 24, 40, 66. 67 |
| Fc fragment of IgG, high affinity 1a, receptor (FCGR1A) | Copy number increase | Immune function | Plausible | IgG receptor I phagocyte deficiency | 40, 56 |
| Follicle stimulating hormone receptor (FSHR) | Positive selection | Decreased gestation/Birth timing | Plausible | Amenorrhea, infertility, ovarian dysgenesis type 1 (premature ovarian failure), ovarian hyperstimulation syndrome | 68, 69 |
| Forkhead box P2 (FOXP2) | Amino acid change/Positive Selection | Language/speech development and increased length of dendrite spines | Definite | Speech-language disorder-1 | 70 |
| Forkhead box D4 (FOXD4) | Novel Gene Variant | Nervous system development | Plausible | Dilated cardiomyopathy, suicidality, OCD | 56 |
| General transcription factor 2-I repeat domain-containing protein 2 (GTF2IRD2) | Copy number increase | Unknown | N/A | Williams-Beuren syndrome | 18, 56 |
| Growth arrest and DNA-damage-inducible, gamma (GADD45G) | Deletion of regulatory DNA/Expression change | Expansion of human forebrain | Plausible | Thyroid carcinoma | 8 |
| Glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A) | Amino acid change/Positive Selection | Learning and memory | Plausible | Unknown | 71 |
| Glutamate receptor, ionotropic, N-methyl-D-aspartate 3B (GRIN3B) | Amino acid change/Positive Selection | Higher brain function | Plausible | Unknown | 71 |
| Human accelerated conserved noncoding region 1 (HACNS1) | Positive Selection | Changes in development of anterior wrist and thumb | Likely | Unknown | 9 |
| Human accelerated region 1 forward (HAR1f) | Positive Selection | Development of neocortex | Plausible | Unknown | 14 |
| Mannose receptor C, type 1 (MRC1) | Novel gene variant | Recovery from inflammation, regulator of glycoprotein homeostasis | Plausible | Leprosy manifestation | 56 |
| Microcephalin 1 (MCPH1) | Positive Selection | Brain Size | Plausible | Microcephaly | 58, 72 |
| Myosin heavy chain 16 (MYH16) | Pseudogene | Cranio-facial musculature and morphology | Plausible | Unknown | 73 |
| Neutrophil cytosolic factor I (NCFI) | Copy number increase | Phagocyte generation of superoxides | Likely | Chronic granulomatous disease, Williams-Beuren syndrome | 56 |
| NLR family, apoptosis inhibitory protein (NAIP) | Copy number increase | Inhibition of apoptosis | Likely | Spinal muscular atrophy | 18, 40, 56 |
| Occludin (OCLN) | Copy number increase | Regulation of TGF-beta, cell migration | Likely | Susceptibility to hepatitis C, Band-like calcification with simplified gyration and polymicrogyria | 18, 56, 74 |
| p21 protein (Cdc42/Rac)-activated kinase 2 (PAK2) | Copy number increase | Neuronal differentiation | Plausible | 3q29 microdeletion syndrome | 18, 75 |
| Peripheral myelin protein 2 (PMP2) | Copy number increase | Myelin stabilization/Protection from demyelination | Plausible | Charcot-Marie-Tooth peroneal muscular atrophy | 18, 76 |
| Phosphodiesterase 4D interacting protein (PDE4DIP) | Copy number increase | Higher brain function | Plausible | Myeloproliferative disorder associated with eosinophilia | 18, 40, 77 |
| Protocadherin 11 X Y linked (PCDH11XY) | Copy number increase/Expression change | Cerebral asymmetry/Language development, neuroendocrine transdifferentiation | Likely | Klinefelter’s syndrome, Alzheimer’s disease, prostate cancer | 18, 78–82 |
| Sialic acid-binding Ig superfamily lectin 5 (SIGLEC5) | Expression change | T-cell hyperactivation due to lowered expression | Likely | Susceptibility to T-cell mediated disease | 64, 83 |
| Sialic acid-binding Ig superfamily lectin 6 (SIGLEC6) | Expression change | Prolonged labor | Plausible | Preeclampsia | 84 |
| Sialic acid-binding Ig superfamily lectin 11 (SIGLEC11) | Gene conversion/Expression change | Alleviation of neurotoxicity from activated microglia. Potential neurotrophic effects. | Likely | Unknown | 85, 86 |
| Sialic acid-binding Ig superfamily lectin 13 (SIGLEC13) | Gene loss | Disease resistance to Sialylated Bacteria | Likely | Unknown | 87 |
| Solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) | Expression change | Metabolic changes in brain and skeletal muscle/Brain size | Plausible | GLUT1 deficiency syndrome 1 and 2, susceptibility to HTLV infection | 88 |
| Solute carrier family 2 (facilitated glucose transporter) member 4 (SLC2A4) | Expression change | Metabolic changes in brain and skeletal muscle/Brain size | Plausible | Noninsulin-dependent diabetes mellitus | 88 |
| Solute carrier family 6 (facilitated glucose transporter) member 13 (SLC6A13) | Copy number increase | Higher brain function | Plausible | Unknown | 18, 89 |
| Survival of motor neurone2, centromeric (SMN2) | Novel gene variant | Motor neuron maintenance, neuronal growth | Likely | Spinal muscular atrophy severity | 18, 56 |
| SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2) | Copy number increase | Increased neuronal branching | Likely | Early infantile epileptic encephalopathy | 18, 20, 25, 40 |
| Sperm protein associated with the nucleus, X-linked family members A/D (SPANXA/D) | Copy number increase | Post-meiotic spermatogenesis | Likely | Unknown | 90, 91 |
| Thrombospondin 4 (THBS4) | Expression change | Synaptic organization and plasticity | Plausible | Familial premature coronary heart disease | 92 |