Darwinian and demographic forces affecting human protein coding genes

Nielsen, Rasmus; Hubisz, Melissa J.; Hellmann, Ines; Torgerson, Dara G.; Andrés, Aida M.; Albrechtsen, Anders; Gutenkunst, Ryan N.; Adams, Mark D.; Cargill, Michele; Boyko, Adam R.; Indap, Amit; Bustamante, Carlos D.; Clark, Andrew G.

doi:10.1101/gr.088336.108

Cited by 144 publications

(160 citation statements)

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“…However, molecular population genetic analyses of selection often focus on detecting selective sweeps driven by positive directional selection in a species-wide sample (Nielsen 2005). Only recently have studies started to scan patterns of gene nucleotide diversity for signatures of selection below the species level, particularly among human regional subpopulations (Tang et al 2007;Nielsen et al 2009;Pickrell et al 2009;Chen et al 2010). …”

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confidence: 99%

Local Selection Across a Latitudinal Gradient Shapes Nucleotide Diversity in Balsam Poplar, Populus balsamifera L

et al. 2011

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Molecular studies of adaptive evolution often focus on detecting selective sweeps driven by positive selection on a specieswide scale; however, much adaptation is local, particularly of ecologically important traits. Here, we look for evidence of range-wide and local adaptation at candidate genes for adaptive phenology in balsam poplar, Populus balsamifera, a widespread forest tree whose range extends across environmental gradients of photoperiod and growing season length. We examined nucleotide diversity of 27 poplar homologs of the flowering-time network-a group of genes that control plant developmental phenology through interactions with environmental cues such as photoperiod and temperature. Only one gene, ZTL2, showed evidence of reduced diversity and an excess of fixed replacement sites, consistent with a species-wide selective sweep. Two other genes, LFY and FRI, harbored high levels of nucleotide diversity and exhibited elevated differentiation between northern and southern accessions, suggesting local adaptation along a latitudinal gradient. Interestingly, FRI has also been identified as a target of local selection between northern and southern accessions of Arabidopsis thaliana, indicating that this gene may be commonly involved in ecological adaptation in distantly related species. Our findings suggest an important role for local selection shaping molecular diversity and reveal limitations of inferring molecular adaptation from analyses designed only to detect species-wide selective sweeps.

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confidence: 99%

Local Selection Across a Latitudinal Gradient Shapes Nucleotide Diversity in Balsam Poplar, Populus balsamifera L

et al. 2011

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“…For a cross-population test, we use the joint frequency spectrum of two populations, referred to as the crosspopulation SFS, or XP-SFS (Sawyer and Hartl 1992;Chen et al 2007;Gutenkunst et al 2009;Nielsen et al 2009). Given two population samples of size n and m, the XP-SFS is defined as a n 3 m matrix j, where the j ij entry represents the number of polymorphic sites at frequency i/n in the first sample, and j/m in the second sample.…”

Section: Population Simulationsmentioning

confidence: 99%

Learning Natural Selection from the Site Frequency Spectrum

Ronen

Udpa

Halperin

et al. 2013

Lecture Notes in Computer Science

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Genetic adaptation to external stimuli occurs through the combined action of mutation and selection. A central problem in genetics is to identify loci responsive to specific selective constraints. Many tests have been proposed to identify the genomic signatures of natural selection by quantifying the skew in the site frequency spectrum (SFS) under selection relative to neutrality. We build upon recent work that connects many of these tests under a common framework, by describing how selective sweeps affect the scaled SFS. We show that the specific skew depends on many attributes of the sweep, including the selection coefficient and the time under selection. Using supervised learning on extensive simulated data, we characterize the features of the scaled SFS that best separate different types of selective sweeps from neutrality. We develop a test, SFselect, that consistently outperforms many existing tests over a wide range of selective sweeps. We apply SFselect to polymorphism data from a laboratory evolution experiment of Drosophila melanogaster adapted to hypoxia and identify loci that strengthen the role of the Notch pathway in hypoxia tolerance, but were missed by previous approaches. We further apply our test to human data and identify regions that are in agreement with earlier studies, as well as many novel regions.N ATURAL selection works by preferentially favoring carriers of beneficial (fit) alleles. At the genetic level, the increased fitness may stem from two sources: either a de novo mutation that is beneficial in the current environment or new environmental stress leading to increased relative fitness of an existing allele. Over time, haplotypes carrying such variants start to dominate the population, causing reduced genetic diversity. This process, known as a selective sweep, is mitigated by recombination and can therefore be observed mostly in the vicinity of the beneficial allele. Improving our ability to detect the genomic signatures of selection is crucial for shedding light on genes responsible for adaptation to environmental stress, including disease.Many tests of neutrality have been proposed based on the site frequency spectrum (Tajima 1989;Fay and Wu 2000;Zeng et al. 2006;Chen et al. 2010;Udpa et al. 2011). We start by describing these tests in a common framework delineated by Achaz (2009). The data, namely genetic variants from a population sample, is typically represented as a matrix with m columns corresponding to segregating sites, and n rows corresponding to individual chromosomes. The sample is chosen from a much larger population of N diploid individuals, where chromosomes are connected by a (hidden) genealogy and mutations occurring in a certain lineage are inherited by all of its descendants ( Figure 1A). Thus, in the example shown in Figure 1A, the mutation at locus 4 appears in four chromosomes from the sample, or 0.5 frequency. Following Fu (1995), let j i denote the number of polymorphic sites at frequency i/n in a sample of size n. The site frequency spectrum (SFS) v...

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“…This is a serious practical concern because many populations of humans, Drosophila, and domesticated species have demographic histories that are far more complex than allowed for by the SNM (Wright et al 2005;Thornton and Andolfatto 2006;Stephan and Li 2007;Gutenkunst et al 2009;Lohmueller et al 2009;Wall et al 2009;vonHoldt et al 2010). One strategy that has been widely employed to deal with the problem of demography is to use a more realistic demographic model to define the critical values of the standard tests of neutrality (Akey et al 2004;Wright et al 2005;Li and Stephan 2006;Thornton and Andolfatto 2006;Nielsen et al 2009). Such an approach should be successful if the demographic model used is a reasonable one.…”

Section: Introductionmentioning

confidence: 99%

Detecting Directional Selection in the Presence of Recent Admixture in African-Americans

Lohmueller

Bustamante

Clark³

2011

Genetics

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We investigate the performance of tests of neutrality in admixed populations using plausible demographic models for African-American history as well as resequencing data from African and AfricanAmerican populations. The analysis of both simulated and human resequencing data suggests that recent admixture does not result in an excess of false-positive results for neutrality tests based on the frequency spectrum after accounting for the population growth in the parental African population. Furthermore, when simulating positive selection, Tajima's D, Fu and Li's D, and haplotype homozygosity have lower power to detect population-specific selection using individuals sampled from the admixed population than from the nonadmixed population. Fay and Wu's H test, however, has more power to detect selection using individuals from the admixed population than from the nonadmixed population, especially when the selective sweep ended long ago. Our results have implications for interpreting recent genome-wide scans for positive selection in human populations. T HE classic model of genetic hitchhiking predicts that a favorable mutation that has recently fixed in the population will be surrounded by reduced heterozygosity (Maynard Smith and Haigh 1974;Kaplan et al. 1989), an excess of low-frequency alleles (Braverman et al. 1995), and an excess of high-frequency derived alleles (Fay and Wu 2000) compared to the expectation under the standard neutral model (SNM). The idea that genetic hitchhiking distorts patterns of genetic variation has been used to derive several statistical tests to evaluate whether one can reject the SNM for a particular region of the genome. Many recent studies have applied tests of neutrality to data from humans (reviewed in Nielsen et al. One complication to the use of statistical tests of neutrality to detect positive selection is that demographic forces can also mimic the patterns of variation expected under genetic hitchhiking (Tajima 1989a;Jensen et al. 2005). Thus, if one rejects neutrality, this could be due to a selective sweep, but it could also be due to the fact that the demographic history of the population is not approximated well by the SNM. This is a serious practical concern because many populations of humans, Drosophila, and domesticated species have demographic histories that are far more complex than allowed for by the SNM (Wright et al. 2005;Thornton and Andolfatto 2006;Stephan and Li 2007;Gutenkunst et al. 2009;Lohmueller et al. 2009;Wall et al. 2009;vonHoldt et al. 2010). One strategy that has been widely employed to deal with the problem of demography is to use a more realistic demographic model to define the critical values of the standard tests of neutrality (Akey et al. 2004;Wright et al. 2005;Li and Stephan 2006;Thornton and Andolfatto 2006;Nielsen et al. 2009). Such an approach should be successful if the demographic model used is a reasonable one. While this is clearly an improvement over using the SNM, the effectiveness of such an approach has not been explored for ver...

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Darwinian and demographic forces affecting human protein coding genes

Cited by 144 publications

References 74 publications

Local Selection Across a Latitudinal Gradient Shapes Nucleotide Diversity in Balsam Poplar, Populus balsamifera L

Local Selection Across a Latitudinal Gradient Shapes Nucleotide Diversity in Balsam Poplar, Populus balsamifera L

Learning Natural Selection from the Site Frequency Spectrum

Detecting Directional Selection in the Presence of Recent Admixture in African-Americans

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