Relaxed selection during a recent human expansion

AbstractHumans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that i) both new and low frequency variants are significantly more deleterious in front than in core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past 6-9 generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection on the wave front. Modeling the evolution of rare variants allowed us to estimate their associated selection coefficients as well as front and core effective sizes. Even though range expansions had a limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions. Since we show that modern human populations are experiencing differential strength of purifying selection, similar processes might have happened throughout human history, contributing to a higher mutation load in populations that have undergone spatial expansions.

Download Full-text

Regions of Lower Crossing Over Harbor More Rare Variants in African Populations ofDrosophila melanogaster

Genetics ◽

10.1093/genetics/158.2.657 ◽

2001 ◽

Vol 158 (2) ◽

pp. 657-665 ◽

Cited By ~ 15

Author(s):

Peter Andolfatto ◽

Molly Przeworski

Keyword(s):

Frequency Spectrum ◽

Nucleotide Diversity ◽

Rare Variants ◽

Purifying Selection ◽

Crossing Over ◽

Background Selection ◽

Deleterious Mutations ◽

African Populations ◽

Rapid Fixation ◽

Parameter Values

AbstractA correlation between diversity levels and rates of recombination is predicted both by models of positive selection, such as hitchhiking associated with the rapid fixation of advantageous mutations, and by models of purifying selection against strongly deleterious mutations (commonly referred to as “background selection”). With parameter values appropriate for Drosophila populations, only the first class of models predicts a marked skew in the frequency spectrum of linked neutral variants, relative to a neutral model. Here, we consider 29 loci scattered throughout the Drosophila melanogaster genome. We show that, in African populations, a summary of the frequency spectrum of polymorphic mutations is positively correlated with the meiotic rate of crossing over. This pattern is demonstrated to be unlikely under a model of background selection. Models of weakly deleterious selection are not expected to produce both the observed correlation and the extent to which nucleotide diversity is reduced in regions of low (but nonzero) recombination. Thus, of existing models, hitchhiking due to the recurrent fixation of advantageous variants is the most plausible explanation for the data.

Download Full-text

The effect of strong purifying selection on genetic diversity

10.1101/211557 ◽

2017 ◽

Author(s):

Ivana Cvijović ◽

Benjamin H. Good ◽

Michael M. Desai

Keyword(s):

Genetic Diversity ◽

Frequency Spectrum ◽

Purifying Selection ◽

Genomic Diversity ◽

Small Samples ◽

Direct Selection ◽

Background Selection ◽

Deleterious Mutations ◽

Site Frequency Spectrum ◽

Neutral Mutations

Purifying selection reduces genetic diversity, both at sites under direct selection and at linked neutral sites. This process, known as background selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background selection are not fully understood. Previous theoretical analyses of this process have taken a backwards-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong purifying selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.

Download Full-text

Distance from sub-Saharan Africa predicts mutational load in diverse human genomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510805112 ◽

2015 ◽

Vol 113 (4) ◽

pp. E440-E449 ◽

Cited By ~ 139

Author(s):

Brenna M. Henn ◽

Laura R. Botigué ◽

Stephan Peischl ◽

Isabelle Dupanloup ◽

Mikhail Lipatov ◽

...

Keyword(s):

Purifying Selection ◽

Allele Frequencies ◽

Sub Saharan Africa ◽

Human Populations ◽

Mutational Load ◽

Deleterious Mutations ◽

High Coverage ◽

Deleterious Alleles ◽

Out Of Africa ◽

Sub Saharan

The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

Download Full-text

Patterns of genetic variability in genomic regions with low rates of recombination

10.1101/739888 ◽

2019 ◽

Cited By ~ 1

Author(s):

Hannes Becher ◽

Benjamin C. Jackson ◽

Brian Charlesworth

Keyword(s):

Genetic Variability ◽

Rare Variants ◽

Genomic Region ◽

Human Populations ◽

Crossing Over ◽

Deleterious Mutations ◽

Effective Population ◽

Genomic Studies ◽

New Perspective ◽

Genomic Regions

SUMMARYSurveys of DNA sequence variation have shown that the level of genetic variability in a genomic region is often strongly positively correlated with its rate of crossing over (CO) [1–3]. This pattern is caused by selection acting on linked sites, which reduces genetic variability and can also cause the frequency distribution of segregating variants to contain more rare variants than expected without selection (skew). These effects of selection may involve the spread of beneficial mutations (selective sweeps, SSWs), the elimination of deleterious mutations (background selection, BGS) or both together, and are expected to be stronger with lower rates of crossing over [1–3]. However, in a recent study of human populations, the skew was reduced in the lowest CO regions compared with regions with somewhat higher CO rates [4]. A similar pattern is seen in the population genomic studies of Drosophila simulans described here. We propose an explanation for this paradoxical observation, and validate it using computer simulations. This explanation is based on the finding that partially recessive, linked deleterious mutations can increase rather than reduce neutral variability when the product of the effective population size (Ne) and the selection coefficient against homozygous carriers of mutations (s) is ≤ 1, i.e. there is associative overdominance (AOD) rather than BGS [5]. We show that AOD can operate in a genomic region with a low rate of CO, opening up a new perspective on how selection affects patterns of variability at linked sites.

Download Full-text

Genomics of a killifish from the Seychelles islands supports transoceanic island colonization and reveals relaxed selection of developmental genes

10.1101/2020.08.03.232421 ◽

2020 ◽

Author(s):

Rongfeng Cui ◽

Alexandra M Tyers ◽

Zahabiya Juzar Malubhoy ◽

Sadie Wisotsky ◽

Stefano Valdesalici ◽

...

Keyword(s):

Purifying Selection ◽

Deleterious Mutations ◽

Effective Population ◽

Relaxed Selection ◽

Annual Killifish ◽

Tectonic Events ◽

Genome Wide ◽

Seychelles Islands ◽

Slightly Deleterious Mutations ◽

Selection Of

AbstractHow freshwater fish colonize remote islands remains an evolutionary puzzle. Tectonic drift and trans-oceanic dispersal models have been proposed as possible alternative mechanisms. Integrating dating of known tectonic events with population genetics and experimental test of salinity tolerance in the Seychelles islands golden panchax (Pachypanchax playfairii), we found support for trans-oceanic dispersal being the most likely scenario. At the macroevolutionary scale, the non-annual killifish golden panchax shows stronger genome-wide purifying selection compared to annual killifishes from continental Africa. Reconstructing past demographies in isolated golden panchax populations provides support for decline in effective population size, which could have allowed slightly deleterious mutations to segregate in the population. Unlike annual killifishes, where relaxed selection preferentially targets aging-related genes, relaxation of purifying selection in golden panchax affects genes involved in developmental processes, including fgf10.

Download Full-text

An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People

Science ◽

10.1126/science.1217876 ◽

2012 ◽

Vol 337 (6090) ◽

pp. 100-104 ◽

Cited By ~ 488

Author(s):

Matthew R. Nelson ◽

Daniel Wegmann ◽

Margaret G. Ehm ◽

Darren Kessner ◽

Pamela St. Jean ◽

...

Keyword(s):

Population Growth ◽

Drug Targets ◽

Complex Disease ◽

Target Genes ◽

Rare Variants ◽

Disease Risk ◽

Growth Parameters ◽

Purifying Selection ◽

Human Populations ◽

Functional Variants

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.

Download Full-text

Distance from Sub-Saharan Africa Predicts Mutational Load in Diverse Human Genomes

10.1101/019711 ◽

2015 ◽

Cited By ~ 6

Author(s):

Brenna M. Henn ◽

Laura R Botigue ◽

Stephan Peischl ◽

Isabelle Dupanloup ◽

Mikhail Lipatov ◽

...

Keyword(s):

Purifying Selection ◽

Allele Frequencies ◽

Sub Saharan Africa ◽

Human Populations ◽

Mutational Load ◽

Deleterious Mutations ◽

High Coverage ◽

Deleterious Alleles ◽

Out Of Africa ◽

Sub Saharan

The Out-of-Africa (OOA) dispersal ~50,000 years ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from 7 geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

Download Full-text

Genetic Engineering of AAV Capsid Gene for Gene Therapy Application

Current Gene Therapy ◽

10.2174/1566523220666200930105521 ◽

2020 ◽

Vol 20 (5) ◽

pp. 321-332

Author(s):

Yunbo Liu ◽

Xu Zhang ◽

Lin Yang

Keyword(s):

Gene Therapy ◽

Neutralizing Antibodies ◽

Human Subjects ◽

Genetic Diseases ◽

Capsid Gene ◽

Human Populations ◽

Stable Gene ◽

Efficient Gene ◽

Gene Therapy Application

Adeno-associated virus (AAV) is a promising vector for in vivo gene therapy because of its excellent safety profile and ability to mediate stable gene expression in human subjects. However, there are still numerous challenges that need to be resolved before this gene delivery vehicle is used in clinical applications, such as the inability of AAV to effectively target specific tissues, preexisting neutralizing antibodies in human populations, and a limited AAV packaging capacity. Over the past two decades, much genetic modification work has been performed with the AAV capsid gene, resulting in a large number of variants with modified characteristics, rendering AAV a versatile vector for more efficient gene therapy applications for different genetic diseases.

Download Full-text

Harmful mutation load in the mitochondrial genomes of cattle breeds

BMC Research Notes ◽

10.1186/s13104-021-05664-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Sankar Subramanian

Keyword(s):

Population Size ◽

Artificial Selection ◽

Deleterious Mutation ◽

Genetic Diseases ◽

Mitochondrial Genomes ◽

Deleterious Mutations ◽

Founder Population ◽

Mutation Load ◽

Effective Population ◽

Cattle Breeds

Abstract Objective Domestication of wild animals results in a reduction in the effective population size, and this could affect the deleterious mutation load of domesticated breeds. Furthermore, artificial selection will also contribute to the accumulation of deleterious mutations due to the increased rate of inbreeding among these animals. The process of domestication, founder population size, and artificial selection differ between cattle breeds, which could lead to a variation in their deleterious mutation loads. We investigated this using mitochondrial genome data from 364 animals belonging to 18 cattle breeds of the world. Results Our analysis revealed more than a fivefold difference in the deleterious mutation load among cattle breeds. We also observed a negative correlation between the breed age and the proportion of deleterious amino acid-changing polymorphisms. This suggests a proportionally higher deleterious SNPs in young breeds compared to older breeds. Our results highlight the magnitude of difference in the deleterious mutations present in the mitochondrial genomes of various breeds. The results of this study could be useful in predicting the rate of incidence of genetic diseases in different breeds.

Download Full-text

The Age of Nonsynonymous and Synonymous Mutations in Animal mtDNA and Implications for the Mildly Deleterious Theory

Genetics ◽

10.1093/genetics/153.1.497 ◽

1999 ◽

Vol 153 (1) ◽

pp. 497-506 ◽

Cited By ~ 4

Author(s):

Rasmus Nielsen ◽

Daniel M Weinreich

Keyword(s):

Dna Sequences ◽

Purifying Selection ◽

Data Sets ◽

Deleterious Mutations ◽

Synonymous Mutations ◽

Weak Evidence ◽

Mitochondrial Data ◽

The Mean ◽

Excess Number ◽

Neutral Mutations

Abstract McDonald/Kreitman tests performed on animal mtDNA consistently reveal significant deviations from strict neutrality in the direction of an excess number of polymorphic nonsynonymous sites, which is consistent with purifying selection acting on nonsynonymous sites. We show that under models of recurrent neutral and deleterious mutations, the mean age of segregating neutral mutations is greater than the mean age of segregating selected mutations, even in the absence of recombination. We develop a test of the hypothesis that the mean age of segregating synonymous mutations equals the mean age of segregating nonsynonymous mutations in a sample of DNA sequences. The power of this age-of-mutation test and the power of the McDonald/Kreitman test are explored by computer simulations. We apply the new test to 25 previously published mitochondrial data sets and find weak evidence for selection against nonsynonymous mutations.

Download Full-text