scholarly journals Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009695
Author(s):  
Chenxing Liu ◽  
Myoung Keun Lee ◽  
Sahin Naqvi ◽  
Hanne Hoskens ◽  
Dongjing Liu ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Human Populations ◽  
Facial Morphology ◽  
Shape Variation ◽  
East African ◽  
Enhancer Activity ◽  
Genome Scans ◽  
Multiple Phenotypes ◽  
Population Comparisons ◽  
Cranial Neural Crest Cells

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.

scholarly journals Genetic basis of body shape variation along the benthic-pelagic axis in cichlid fishes

2021 ◽  
Author(s):  
Leah DeLorenzo ◽  
Destiny Mathews ◽  
A. Allyson Brandon ◽  
Mansi Joglekar ◽  
Aldo Carmona Baez ◽  
...  
Keyword(s):  
Adaptive Radiation ◽  
Body Shape ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Lake Malawi ◽  
Shape Variation ◽  
East African ◽  
Cichlid Fishes ◽  
African Rift ◽  
Two Hybrid

Divergence along the benthic-pelagic axis is one of the most widespread and repeated patterns of morphological variation in fishes, producing body shape diversity associated with ecology and swimming mechanics. This ecological shift is also the first stage of the explosive adaptive radiation of cichlid fishes in the East African Rift Lakes. We use two hybrid crosses of cichlids (Metriaclima sp. x Aulonocara sp. and Labidochromis sp. x Labeotropheus sp., >975 animals total) along the benthic-pelagic ecomorphological axis to determine the genetic basis of body shape diversification. Using a series of both linear and geometric shape measurements, we identify 55 quantitative trait loci (QTL) that underlie various aspects of body shape variation associated with benthic-pelagic divergence. These QTL are spread throughout the genome, each explain 3.0-7.2% of phenotypic variation, and are largely modular. Further, QTL are distinct both between these two crosses of Lake Malawi cichlids and compared to previously identified QTL for body shape in fishes such as sticklebacks. We find that body shape is controlled by many genes of small effects. In all, we find that convergent benthic and pelagic body phenotypes commonly observed across fish clades are most likely due to distinct genetic and molecular mechanisms.

scholarly journals An Engrailed1 enhancer underlies human thermoregulatory evolution

2020 ◽  
Author(s):  
Daniel Aldea ◽  
Yuji Atsuta ◽  
Blerina Kokalari ◽  
Stephen Schaffner ◽  
Bailey Warder ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Mouse Skin ◽  
Human Keratinocytes ◽  
Eccrine Sweat Gland ◽  
Recurrent Mutation ◽  
Eccrine Gland ◽  
Enhancer Activity ◽  
Eccrine Glands ◽  
Human Ortholog ◽  
Altered Regulation

SummaryHumans rely on sweating to cool off and have the highest eccrine sweat gland density among mammals. We investigated whether altered regulation of the Engrailed 1 (EN1) gene, the levels of which are critical for patterning eccrine glands during development, could underlie the evolution of this defining human trait. First, we identify five EN1 candidate enhancers (ECEs) using comparative genomics and validation of enhancer activity in mouse skin. The human ortholog of one ECE, hECE18, contains multiple derived substitutions that together dramatically increase the activity of this enhancer in keratinocytes. Targeted repression of hECE18 reduces EN1 expression in human keratinocytes, indicating hECE18 upregulates EN1 in this context. Finally, we find that hECE18 increases ectodermal En1 in a humanized knock-in mouse to increase eccrine gland number. Our study uncovers a genetic basis for the evolution of one of the most singular human adaptations and implicates the recurrent mutation of a single enhancer as a novel mechanism for evolutionary change.

scholarly journals Genetics of Lactose Intolerance: An Updated Review and Online Interactive World Maps of Phenotype and Genotype Frequencies

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2689
Author(s):  
Augusto Anguita-Ruiz ◽  
Concepción M. Aguilera ◽  
Ángel Gil
Keyword(s):  
Genetic Basis ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genotype Frequencies ◽  
Genetic Mechanisms ◽  
Visualization Tools ◽  
Available Information ◽  
Static World ◽  
Interactive Resources

In humans the ability to digest milk lactose is conferred by a β-galactosidase enzyme called lactase-phlorizin hydrolase (LPH). While in some humans (approximately two-thirds of humankind) the levels of this enzyme decline drastically after the weaning phase (a trait known as lactase non-persistence (LNP)), some other individuals are capable of maintaining high levels of LPH lifelong (lactase persistence (LP)), thus being able to digest milk during adulthood. Both lactase phenotypes in humans present a complex genetic basis and have been widely investigated during the last decades. The distribution of lactase phenotypes and their associated single nucleotide polymorphisms (SNPs) across human populations has also been extensively studied, though not recently reviewed. All available information has always been presented in the form of static world maps or large dimension tables, so that it would benefit from the newly available visualization tools, such as interactive world maps. Taking all this into consideration, the aims of the present review were: (1) to gather and summarize all available information on LNP and LP genetic mechanisms and evolutionary adaptation theories, and (2) to create online interactive world maps, including all LP phenotype and genotype frequency data reported to date. As a result, we have created two online interactive resources, which constitute an upgrade over previously published static world maps, and allow users a personalized data exploration, while at the same time accessing complete reports by population or ethnicity.

scholarly journals The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks

2012 ◽  
Vol 13 (2) ◽  
pp. 239 ◽  
Author(s):  
Tatiana V Morozova ◽  
David Goldman ◽  
Trudy FC Mackay ◽  
Robert RH Anholt
Keyword(s):  
Complex Networks ◽  
Genetic Basis ◽  
Multiple Phenotypes

scholarly journals Genetic architecture of natural variation in visual senescence in Drosophila

2016 ◽  
Vol 113 (43) ◽  
pp. E6620-E6629 ◽  
Author(s):  
Mary Anna Carbone ◽  
Akihiko Yamamoto ◽  
Wen Huang ◽  
Rachel A. Lyman ◽  
Tess Brune Meadors ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Genetic Variation ◽  
Life Span ◽  
Candidate Genes ◽  
Natural Variation ◽  
Genetic Basis ◽  
Nervous System Development ◽  
Interindividual Variation ◽  
Human Populations ◽  
Age Dependent

Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.

scholarly journals Genetic Basis of Variation in Cocaine and Methamphetamine Consumption in Outbred Populations of Drosophila melanogaster

2021 ◽  
Author(s):  
Brandon M. Baker ◽  
Mary Anna Carbone ◽  
Wen Huang ◽  
Robert R. H. Anholt ◽  
Trudy F. C. Mackay
Keyword(s):  
Nervous System ◽  
Drosophila Melanogaster ◽  
Genetic Basis ◽  
Genetic Model ◽  
System Development ◽  
Gene Interaction ◽  
Nervous System Development ◽  
Drug Consumption ◽  
Human Populations ◽  
And Function

AbstractWe used Drosophila melanogaster to map the genetic basis of naturally occurring variation in voluntary consumption of cocaine and methamphetamine. We derived an outbred advanced intercross population (AIP) from 37 sequenced inbred wild-derived lines of the Drosophila melanogaster Genetic Reference Panel (DGRP), which are maximally genetically divergent, have minimal residual heterozygosity, are not segregating for common inversions, and are not infected with Wolbachia pipientis. We assessed consumption of sucrose, methamphetamine-supplemented sucrose and cocaine-supplemented sucrose, and found considerable phenotypic variation for consumption of both drugs, in both sexes. We performed whole genome sequencing and extreme QTL mapping on the top 10% of consumers for each replicate, sex and condition, and an equal number of randomly selected flies. We evaluated changes in allele frequencies among high consumers and control flies and identified 3,033 variants significantly (P < 1.9 × 10-8) associated with increased consumption, located in or near 1,962 genes. Many of these genes are associated with nervous system development and function, and 77 belong to a known gene-gene interaction subnetwork. We assessed the effects of RNA interference (RNAi) on drug consumption for 22 candidate genes; 17 had a significant effect in at least one sex. We constructed allele-specific AIPs which were homozygous for alternative candidate alleles for 10 SNPs and measured average consumption for each population; nine SNPs had significant effects in at least one sex. The genetic basis of voluntary drug consumption in Drosophila is polygenic and implicates genes with human orthologs and associated variants with sex- and drug-specific effects.Significance StatementThe use of cocaine and methamphetamine presents significant socioeconomic problems. However, identifying the genetic underpinnings that determine susceptibility to substance use is challenging in human populations. The fruit fly, Drosophila melanogaster, presents a powerful genetic model since we can control the genetic background and environment, 75% of disease-causing genes in humans have a fly counterpart, and flies - like humans - exhibit adverse effects upon cocaine and methamphetamine exposure. We showed that the genetic architecture underlying variation in voluntary cocaine and methamphetamine consumption differs between sexes and is dominated by variants in genes associated with connectivity and function of the nervous system. Results obtained from the Drosophila gene discovery model can guide studies on substance abuse susceptibility in human populations.

scholarly journals Insights into the genetic architecture of the human face

2020 ◽  
Author(s):  
Julie D. White ◽  
Karlijne Indencleef ◽  
Sahin Naqvi ◽  
Ryan J. Eller ◽  
Jasmien Roosenboom ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Cell Types ◽  
Human Face ◽  
Normal Range ◽  
Enhancer Activity ◽  
Limb Morphogenesis ◽  
Cranial Neural Crest Cells ◽  
Genomic Regions

AbstractThe human face is complex and multipartite, and characterization of its genetic architecture remains intriguingly challenging. Applying GWAS to multivariate shape phenotypes, we identified 203 genomic regions associated with normal-range facial variation, 117 of which are novel. The associated regions are enriched for both genes relevant to craniofacial and limb morphogenesis and enhancer activity in cranial neural crest cells and craniofacial tissues. Genetic variants grouped by their contribution to similar aspects of facial variation show high within-group correlation of enhancer activity, and four SNP pairs display evidence of epistasis, indicating potentially coordinated actions of variants within the same cell types or tissues. In sum, our analyses provide new insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.

scholarly journals pmTR database: population matched (PM) germline allelic variants of T-cell receptor (TR) loci

2020 ◽  
Author(s):  
Julian Dekker ◽  
Jacques J.M. van Dongen ◽  
Marcel J.T. Reinders ◽  
Indu Khatri
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Receptor ◽  
Genetic Basis ◽  
Cell Receptor ◽  
Human Populations ◽  
Allelic Variants ◽  
Asian Populations ◽  
African Populations ◽  
Source Of Information

AbstractT-cell receptor (TR) germline alleles are arranged, organized and made available to the research community by the IMGT database. This state-of-the-art database, however, does not provide information regarding population specificity and allelic frequencies of the genes all four human TR loci (TRA, TRB, TRG and TRD). The specificity of allelic variants to different human populations can, however, be a rich source of information when studying the genetic basis of population-specific immune responses in vaccination and disease. To make TR germline alleles available for such population-specific studies, we meticulously identified true germline alleles enriched with complete TR allele sequences and their frequencies across 26 different human populations, profiled by “1,000 Genomes data”. We identified 205 TRAV, 249 TRBV, 16 TRGV and 5 TRDV germline alleles supported by at least four haplotypes (= minimum of two individuals). The diversity of germline allelic variants in the TR loci is highest in Africans followed by Non-African populations. A majority of the Non-African alleles are specific to the Asian populations, suggesting a diverse profile of TR germline alleles in different human populations. Interestingly, the alleles known in the IMGT database are frequent and common across all the superpopulations. We believe that this new set of genuine germline TR sequences represents a valuable new resource which we have made available through the new population-matched TR (pmTR) database, accessible via https://pmtrig.lumc.nl/.

scholarly journals Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution

2021 ◽  
Vol 118 (16) ◽  
pp. e2021722118
Author(s):  
Daniel Aldea ◽  
Yuji Atsuta ◽  
Blerina Kokalari ◽  
Stephen F. Schaffner ◽  
Rexxi D. Prasasya ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Natural Variation ◽  
Genetic Basis ◽  
Eccrine Sweat Gland ◽  
Evolutionary Adaptation ◽  
Human Lineage ◽  
Eccrine Gland ◽  
Enhancer Activity ◽  
Cultured Keratinocytes ◽  
Eccrine Glands

Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans’ high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.

scholarly journals Genomic regions controlling shape variation in the first upper molar of the house mouse

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Luisa F Pallares ◽  
Ronan Ledevin ◽  
Sophie Pantalacci ◽  
Leslie M Turner ◽  
Eirikur Steingrimsson ◽  
...  
Keyword(s):  
Phenotypic Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Shape Variation ◽  
Tooth Shape ◽  
Mus Musculus Musculus ◽  
Genome Wide ◽  
Genomic Regions ◽  
Hybrid Mice ◽  
Upper Molar

Numerous loci of large effect have been shown to underlie phenotypic variation between species. However, loci with subtle effects are presumably more frequently involved in microevolutionary processes but have rarely been discovered. We explore the genetic basis of shape variation in the first upper molar of hybrid mice between Mus musculus musculus and M. m. domesticus. We performed the first genome-wide association study for molar shape and used 3D surface morphometrics to quantify subtle variation between individuals. We show that many loci of small effect underlie phenotypic variation, and identify five genomic regions associated with tooth shape; one region contained the gene microphthalmia-associated transcription factor Mitf that has previously been associated with tooth malformations. Using a panel of five mutant laboratory strains, we show the effect of the Mitf gene on tooth shape. This is the first report of a gene causing subtle but consistent variation in tooth shape resembling variation in nature.

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