scholarly journals The counteracting effects of demography on functional genomic variation: the Roma paradigm

2021 ◽  
Author(s):  
Neus Font-Porterias ◽  
Rocio Caro-Consuegra ◽  
Marcel Lucas-Sánchez ◽  
Marie Lopez ◽  
Aaron Giménez ◽  
...  
Keyword(s):  
Gene Flow ◽  
Rare Variants ◽  
Demographic History ◽  
Genomic Variation ◽  
Human Populations ◽  
History Plays ◽  
High Coverage ◽  
Roma Population ◽  
Genome Wide ◽  
Whole Exome

Abstract Demographic history plays a major role in shaping the distribution of genomic variation. Yet the interaction between different demographic forces and their effects in the genomes is not fully resolved in human populations. Here we focus on the Roma population, the largest transnational ethnic minority in Europe. They have a South Asian origin and their demographic history is characterized by recent dispersals, multiple founder events and extensive gene flow from non-Roma groups. Through the analyses of new high-coverage whole exome sequences and genome-wide array data for 89 Iberian Roma individuals together with forward simulations, we show that founder effects have reduced their genetic diversity and proportion of rare variants, gene flow has counteracted the increase in mutational load, runs of homozygosity show ancestry-specific patterns of accumulation of deleterious homozygotes, and selection signals primarily derive from pre-admixture adaptation in the Roma population sources. The present study shows how two demographic forces, bottlenecks and admixture, act in opposite directions and have long-term balancing effects on the Roma genomes. Understanding how demography and gene flow shape the genome of an admixed population provides an opportunity to elucidate how genomic variation is modelled in human populations.

scholarly journals Genome diversity in Ukraine

GigaScience ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Taras K Oleksyk ◽  
Walter W Wolfsberger ◽  
Alexandra M Weber ◽  
Khrystyna Shchubelka ◽  
Olga T Oleksyk ◽  
...  
Keyword(s):  
Sequence Data ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
High Coverage ◽  
Genome Data ◽  
New Information ◽  
Genome Wide ◽  
Public Data ◽  
Genome Wide Data ◽  
Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

scholarly journals The great tit HapMap project: a continental-scale analysis of genomic variation in a songbird

2019 ◽  
Author(s):  
Lewis G. Spurgin ◽  
Mirte Bosse ◽  
Frank Adriaensen ◽  
Tamer Albayrak ◽  
Christos Barboutis ◽  
...  
Keyword(s):  
Positive Selection ◽  
Recombination Rate ◽  
Demographic History ◽  
Great Tit ◽  
Genomic Variation ◽  
Genomic Diversity ◽  
Hapmap Project ◽  
Widespread Species ◽  
Continental Scale ◽  
Genome Wide

AbstractA major aim of evolutionary biology is to understand why patterns of genomic diversity vary among populations and species. Large-scale genomic studies of widespread species are useful for studying how the environment and demographic history shape patterns of genomic divergence, and with the continually decreasing cost of sequencing and genotyping, such studies are now becoming feasible. Here, we carry out one of the most geographically comprehensive surveys of genomic variation in a wild vertebrate to date; the great tit (Parus major) HapMap project. We screened ca 500,000 SNP markers across 647 individuals from 29 populations, spanning almost the entire geographic range of the European great tit subspecies. We found that genome-wide variation was consistent with a recent colonisation across Europe from a single refugium in South-East Europe, with bottlenecks and reduced genetic diversity in island populations. Differentiation across the genome was highly heterogeneous, with clear “islands of differentiation” even among populations with very low levels of genome-wide differentiation. Low local recombination rate in the genome was a strong predictor of high local genomic differentiation (FST), especially in island and peripheral mainland populations, suggesting that the interplay between genetic drift and recombination is a key driver of highly heterogeneous differentiation landscapes. We also detected genomic outlier regions that were confined to one or more peripheral great tit populations, most likely as a result of recent directional selection at the range edges of this species. Haplotype-based measures of selection were also related to recombination rate, albeit less strongly, and highlighted population-specific sweeps that likely resulted from positive selection. These regions under positive selection contained candidate genes associated with morphology, thermal adaptation and colouration, providing promising avenues for future investigation. Our study highlights how comprehensive screens of genomic variation in wild organisms can provide unique insights into evolution.

SMARCA2 common variant association and rare variant excess in Schizophrenia patients from an Algerian Trio Cohort

2011 ◽  
Vol 26 (S2) ◽  
pp. 1346-1346
Author(s):  
D. Benmessaoud ◽  
A.-M. Lepagnol-Bestel ◽  
M. Delepine ◽  
J. Hager ◽  
J.-M. Moalic ◽  
...  
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Fisher Test ◽  
Coding Regions ◽  
Genome Wide ◽  
Whole Exome ◽  
Positive Evolution

Genome wide association studies (GWAS) of Schizophrenia (SZ) patients have identified common variants in ten genes including SMARCA2 (Koga et al., HMG, 2009). We found that the SZ-GWAS genes are part of an interacting network centered on SMARCA2 (Loe-Mie et al., HMG, 2010). Furthermore, SMARCA2 was found disrupted in SZ (Walsh et al., Science, 2008). SMARCA2 encodes the ATPase (BRM) of the SWI/SNF chromatin remodeling complex that is at the interface of genome and environmental adaptation.Taking advantage of an Algerian trio cohort of one hundred SZ patients (Benmessaoud et al., BMC Psychiatry, 2008), we replicated the association of SNP rs2296212 localized in exon 33, already shown associated in Koga study and resulting in D1546E amino acid change in the SMARCA2 protein. We studied SMARCA2 codons and found that exon 33 displays a signature of positive evolution in the primate lineage.Our working hypothesis is that the coding regions displaying positive selection are target of novel rare variants. To address this question, we sequenced two exons displaying positive evolution and one exon without evidence of positive evolution.We found (i) that rare variants are significantly in excess in SZ-patients compared to their parents (p = 0.038, Fisher test) and (ii) a higher proportion of rare variants in the primate-accelerated exons compared with the non-evolutionary exon in SZ-patients (p = 0.032, Fisher test).SMARCA2 exon sequencing and whole exome sequencing from patients harboring SNP rs2296212 common variant are under progress. Altogether, these results are expected to give new insights into the genetic architecture of SZ.

scholarly journals Genomic divergence in allopatric Northern Cardinals of the North American warm deserts is associated with behavioral differentiation

2018 ◽  
Author(s):  
Kaiya L. Provost ◽  
William M. Mauck ◽  
Brian Tilston Smith
Keyword(s):  
Gene Flow ◽  
Sonoran Desert ◽  
Demographic History ◽  
Isolation With Migration ◽  
Song Recognition ◽  
Behavioral Isolation ◽  
The North ◽  
Genome Wide ◽  
Behavioral Differentiation ◽  
Northern Cardinals

ABSTRACTBiogeographic barriers are thought to be important in initiating speciation through geographic isolation, but they rarely indiscriminately and completely reduce gene flow across the entire community. Understanding which species’ attributes regulate a barrier could help elucidate how speciation is initiated. Here, we investigated the association of behavioral isolation on population differentiation in Northern Cardinals (Cardinalis cardinalis) distributed across the Cochise Filter Barrier, a region of transitional habitat which separates the Sonoran and Chihuahuan deserts. Using genome-wide markers, we modeled demographic history by fitting the data to isolation and isolation-with-migration models. The best-fit model indicated that desert populations diverged in the mid-Pleistocene and there has been historically low, unidirectional gene flow into the Sonoran Desert. We then tested song recognition using reciprocal call-broadcast experiments to compare song recognition between deserts, controlling for song dialect changes within deserts. We found that male Northern Cardinals in both deserts were most aggressive to local songs and failed to recognize across-barrier songs. A correlation of genomic differentiation despite historic introgression and strong song discrimination is consistent with a model where speciation is initiated across a barrier and maintained by behavioral isolation.

scholarly journals The genetic scenario of Mercheros: an under-represented group within the Iberian Peninsula

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
André Flores-Bello ◽  
Neus Font-Porterias ◽  
Julen Aizpurua-Iraola ◽  
Sara Duarri-Redondo ◽  
David Comas
Keyword(s):  
Iberian Peninsula ◽  
Demographic History ◽  
Ethnically Diverse ◽  
Human Populations ◽  
Minority Ethnic Group ◽  
Fine Scale ◽  
Genome Wide ◽  
Wide Range ◽  
Y Chromosome Str ◽  
Western Eurasia

Abstract Background The general picture of human genetic variation has been vastly depicted in the last years, yet many populations remain broadly understudied. In this work, we analyze for the first time the Merchero population, a Spanish minority ethnic group that has been scarcely studied and historically persecuted. Mercheros have been roughly characterised by an itinerant history, common traditional occupations, and the usage of their own language. Results Here, we examine the demographic history and genetic scenario of Mercheros, by using genome-wide array data, whole mitochondrial sequences, and Y chromosome STR markers from 25 individuals. These samples have been complemented with a wide-range of present-day populations from Western Eurasia and North Africa. Our results show that the genetic diversity of Mercheros is explained within the context of the Iberian Peninsula, evidencing a modest signal of Roma admixture. In addition, Mercheros present low genetic isolation and intrapopulation heterogeneity. Conclusions This study represents the first genetic characterisation of the Merchero population, depicting their fine-scale ancestry components and genetic scenario within the Iberian Peninsula. Since ethnicity is not only influenced by genetic ancestry but also cultural factors, other studies from multiple disciplines are needed to further explore the Merchero population. As with Mercheros, there is a considerable gap of underrepresented populations and ethnic groups in publicly available genetic data. Thus, we encourage the consideration of more ethnically diverse population panels in human genetic studies, as an attempt to improve the representation of human populations and better reconstruct their fine-scale history.

scholarly journals The genomic impact of European colonization of the Americas

2019 ◽  
Author(s):  
Linda Ongaro ◽  
Marilia O. Scliar ◽  
Rodrigo Flores ◽  
Alessandro Raveane ◽  
Davide Marnetto ◽  
...  
Keyword(s):  
Gene Flow ◽  
Demographic History ◽  
Colonial Era ◽  
Genome Wide ◽  
A Genome ◽  
European Colonization ◽  
High Degree ◽  
The Impact ◽  
North And South America ◽  
North And South

AbstractThe human genetic diversity of the Americas has been shaped by several events of gene flow that have continued since the Colonial Era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored.Here we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected i) the genetic structure, ii) the admixture profile, iii) the demographic history and iv) sex-biased gene-flow dynamics, of the Americas.We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East and to specific regions of Africa.

scholarly journals Tracking human population structure through time from whole genome sequences

2019 ◽  
Author(s):  
Ke Wang ◽  
Iain Mathieson ◽  
Jared O’Connell ◽  
Stephan Schiffels
Keyword(s):  
Population Structure ◽  
Gene Flow ◽  
Demographic History ◽  
Time Dependent ◽  
Human Populations ◽  
Whole Genome ◽  
Genome Sequences ◽  
Migration Model ◽  
Novel Approach ◽  
Different Populations

AbstractThe genetic diversity of humans, like many species, has been shaped by a complex pattern of population separations followed by isolation and subsequent admixture. This pattern, reaching at least as far back as the appearance of our species in the paleontological record, has left its traces in our genomes. Reconstructing a population’s history from these traces is a challenging problem. Here we present a novel approach based on the Multiple Sequentially Markovian Coalescent (MSMC) to analyse the population separation history. Our approach, called MSMC-IM, uses an improved implementation of the MSMC (MSMC2) to estimate coalescence rates within and across pairs of populations, and then fits a continuous Isolation-Migration model to these rates to obtain a time-dependent estimate of gene flow. We show, using simulations, that our method can identify complex demographic scenarios involving post-split admixture or archaic introgression. We apply MSMC-IM to whole genome sequences from 15 worldwide populations, tracking the process of human genetic diversification. We detect traces of extremely deep ancestry between some African populations, with around 1% of ancestry dating to divergences older than a million years ago.Author SummaryHuman demographic history is reflected in specific patterns of shared mutations between the genomes from different populations. Here we aim to unravel this pattern to infer population structure through time with a new approach, called MSMC-IM. Based on estimates of coalescence rates within and across populations, MSMC-IM fits a time-dependent migration model to the pairwise rate of coalescences. We implemented this approach as an extension to existing software (MSMC2), and tested it with simulations exhibiting different histories of admixture and gene flow. We then applied it to the genomes from 15 worldwide populations to reveal their pairwise separation history ranging from a few thousand up to several million years ago. Among other results, we find evidence for remarkably deep population structure in some African population pairs, suggesting that deep ancestry dating to one million years ago and older is still present in human populations in small amounts today.

scholarly journals Gene Flow and Natural Selection in Oceanic Human Populations Inferred from Genome-Wide SNP Typing

2008 ◽  
Vol 25 (8) ◽  
pp. 1750-1761 ◽  
Author(s):  
R. Kimura ◽  
J. Ohashi ◽  
Y. Matsumura ◽  
M. Nakazawa ◽  
T. Inaoka ◽  
...  
Keyword(s):  
Gene Flow ◽  
Natural Selection ◽  
Human Populations ◽  
Snp Typing ◽  
Genome Wide

scholarly journals Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

2017 ◽  
Vol 103 (2) ◽  
pp. 649-659 ◽  
Author(s):  
Sasha R Howard ◽  
Leonardo Guasti ◽  
Ariel Poliandri ◽  
Alessia David ◽  
Claudia P Cabrera ◽  
...  
Keyword(s):  
Body Mass ◽  
Rare Variants ◽  
Association Studies ◽  
Delayed Puberty ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Whole Exome ◽  
Timing Of Puberty

Abstract Context Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity–associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/− mice. Results We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/− mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.

scholarly journals Efficient and Flexible Integration of Variant Characteristics in Rare Variant Association Studies Using Integrated Nested Laplace Approximation

2020 ◽  
Author(s):  
Hana Susak ◽  
Laura Serra-Saurina ◽  
Raquel Rabionet Janssen ◽  
Laura Domènech ◽  
Mattia Bosio ◽  
...  
Keyword(s):  
Statistical Methods ◽  
Genome Sequencing ◽  
Rare Variant ◽  
Rare Variants ◽  
Association Studies ◽  
Complex Diseases ◽  
Phenotypic Variance ◽  
Rare Variant Association ◽  
Genome Wide ◽  
Whole Exome

AbstractRare variants are thought to play an important role in the etiology of complex diseases and may explain a significant fraction of the missing heritability in genetic disease studies. Next-generation sequencing facilitates the association of rare variants in coding or regulatory regions with complex diseases in large cohorts at genome-wide scale. However, rare variant association studies (RVAS) still lack power when cohorts are small to medium-sized and if genetic variation explains a small fraction of phenotypic variance. Here we present a novel Bayesian rare variant Association Test using Integrated Nested Laplace Approximation (BATI). Unlike existing RVAS tests, BATI allows integration of individual or variant-specific features as covariates, while efficiently performing inference based on full model estimation. We demonstrate that BATI outperforms established RVAS methods on realistic, semi-synthetic whole-exome sequencing cohorts, especially when using meaningful biological context, such as functional annotation. We show that BATI achieves power above 75% in scenarios in which competing tests fail to identify risk genes, e.g. when risk variants in sum explain less than 0.5% of phenotypic variance. We have integrated BATI, together with five existing RVAS tests in the ‘Rare Variant Genome Wide Association Study’ (rvGWAS) framework for data analyzed by whole-exome or whole genome sequencing. rvGWAS supports rare variant association for genes or any other biological unit such as promoters, while allowing the analysis of essential functionalities like quality control or filtering. Applying rvGWAS to a Chronic Lymphocytic Leukemia study we identified eight candidate predisposition genes, including EHMT2 and COPS7A.Data availability and implementationAll relevant data are within the manuscript and pipeline implementation on https://github.com/hanasusak/rvGWASAuthor summaryComplex diseases are characterized by being related to genetic factors and environmental factors such as air pollution, diet etc. that together define the susceptibility of each individual to develop a given disease. Much effort has been applied to advance the knowledge of the genetic bases of such diseases, specially in the discovery of frequent genetic variants in the population increasing disease risk. However, these variants usually explain a little part of the etiology of such diseases. Previous studies have shown that rare variants, i.e. variants present in less than 1% of the population, may explain the rest of the variability related to genetic aspects of the disease.Genome sequencing offers the opportunity to discover rare variants, but powerful statistical methods are needed to discriminate those variants that induce susceptibility to the disease. Here we have developed a powerful and flexible statistical approach for the detection of rare variants associated with a disease and we have integrated it into a computer tool that is easy and intuitive for the researchers and clinicians to use. We have shown that our approach outperformed other common statistical methods specially in a situation where these variants explain just a small part of the disease. The discovery of these rare variants will contribute to the knowledge of the molecular mechanism of complex diseases.

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