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Inference of Evolutionary Forces Acting on Human Biological Pathways.

Daub JT, Dupanloup I, Robinson-Rechavi M, Excoffier L - Genome Biol Evol (2015)

Bottom Line: Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways.This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets.For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

View Article: PubMed Central - PubMed

Affiliation: CMPG, Institute of Ecology and Evolution, University of Berne, Switzerland Swiss Institute of Bioinformatics SIB, Lausanne, Switzerland Present address: Institute of Evolutionary Biology (UPF-CSIC), Barcelona, Spain josephine.daub@upf.edu laurent.excoffier@iee.unibe.ch.

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Results from the 2DNS test. Here, shared SNPs (SNPs that are polymorphic both in African and non-African populations) are compared with fixed substitutions in the human branch. (A) Distribution of DN/DS and PN/PS ratios of all tested pathways. Each dot represents a pathway with color corresponding to its significance and size to its total exon length. The six pathways that scored significant (q value < 0.2; table 2) in the 2DNS test are highlighted by a black circle. Note that seemingly outlier gene sets may not reach significance due to their small size, which increases the variance of their  distribution. For example, the Hormone ligand-binding receptors pathway (depicted in gray; H), has a high DN/DS ratio, but because of its small size (ten genes, 24 kb total exon length) its  distribution is very widespread in the 2D space. (B–G) Null distributions for six significant (q < 0.2) pathways. (H) Null distribution for the Hormone ligand-binding receptors pathway as a typical example of a nonsignificant outlier. The observed positions of gene sets are indicated as orange dots highlighted by a black circle in the DN/DS–PN/PS plane, whereas the empirical  distribution is shown as gray dots (N = 400,000). Light-orange dots show the scores of the jackknifed gene sets. The contour lines mark the proportion (0.5, 0.9, and 0.99) of the  distribution that falls within these areas.
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evv083-F1: Results from the 2DNS test. Here, shared SNPs (SNPs that are polymorphic both in African and non-African populations) are compared with fixed substitutions in the human branch. (A) Distribution of DN/DS and PN/PS ratios of all tested pathways. Each dot represents a pathway with color corresponding to its significance and size to its total exon length. The six pathways that scored significant (q value < 0.2; table 2) in the 2DNS test are highlighted by a black circle. Note that seemingly outlier gene sets may not reach significance due to their small size, which increases the variance of their distribution. For example, the Hormone ligand-binding receptors pathway (depicted in gray; H), has a high DN/DS ratio, but because of its small size (ten genes, 24 kb total exon length) its distribution is very widespread in the 2D space. (B–G) Null distributions for six significant (q < 0.2) pathways. (H) Null distribution for the Hormone ligand-binding receptors pathway as a typical example of a nonsignificant outlier. The observed positions of gene sets are indicated as orange dots highlighted by a black circle in the DN/DS–PN/PS plane, whereas the empirical distribution is shown as gray dots (N = 400,000). Light-orange dots show the scores of the jackknifed gene sets. The contour lines mark the proportion (0.5, 0.9, and 0.99) of the distribution that falls within these areas.

Mentions: Human single-nucleotide polymorphisms (SNPs) were inferred from the comparison of the whole genomes of 42 unrelated individuals sequenced by Complete Genomics (CG) at a depth of 51–89X coverage per genome (Drmanac et al. 2010). The 42 individuals were sampled in 3 African populations (four Luhya from Webuye, Kenya; four Maasai from Kinyawa, Kenya; and nine Yoruba from Ibadan, Nigeria), and 5 non-African populations (nine Utah residents with Northern and Western European ancestry from the CEPH collection; four Han Chinese from Beijing; four Gujarati Indians from Houston, TX; four Japanese from Tokyo; and four Toscans from Italy). The SNPs were divided into three categories: Sites which are polymorphic in Africans only (African SNPs), sites polymorphic in non-Africans only (non-African SNPs), and sites polymorphic in both Africans and non-Africans (shared SNPs). The shared SNPs presumably arose before the migration of modern humans out of Africa and are therefore depleted from recent deleterious mutations that otherwise could distort selective signals. This group of SNPs was used in the 2DNS test (fig. 1 and supplementary fig. S1, Supplementary Material online). The African and non-African SNPs were used in a further analysis to compare demographic patterns between the two regions (fig. 2).Fig. 1.—


Inference of Evolutionary Forces Acting on Human Biological Pathways.

Daub JT, Dupanloup I, Robinson-Rechavi M, Excoffier L - Genome Biol Evol (2015)

Results from the 2DNS test. Here, shared SNPs (SNPs that are polymorphic both in African and non-African populations) are compared with fixed substitutions in the human branch. (A) Distribution of DN/DS and PN/PS ratios of all tested pathways. Each dot represents a pathway with color corresponding to its significance and size to its total exon length. The six pathways that scored significant (q value < 0.2; table 2) in the 2DNS test are highlighted by a black circle. Note that seemingly outlier gene sets may not reach significance due to their small size, which increases the variance of their  distribution. For example, the Hormone ligand-binding receptors pathway (depicted in gray; H), has a high DN/DS ratio, but because of its small size (ten genes, 24 kb total exon length) its  distribution is very widespread in the 2D space. (B–G) Null distributions for six significant (q < 0.2) pathways. (H) Null distribution for the Hormone ligand-binding receptors pathway as a typical example of a nonsignificant outlier. The observed positions of gene sets are indicated as orange dots highlighted by a black circle in the DN/DS–PN/PS plane, whereas the empirical  distribution is shown as gray dots (N = 400,000). Light-orange dots show the scores of the jackknifed gene sets. The contour lines mark the proportion (0.5, 0.9, and 0.99) of the  distribution that falls within these areas.
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Related In: Results  -  Collection

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evv083-F1: Results from the 2DNS test. Here, shared SNPs (SNPs that are polymorphic both in African and non-African populations) are compared with fixed substitutions in the human branch. (A) Distribution of DN/DS and PN/PS ratios of all tested pathways. Each dot represents a pathway with color corresponding to its significance and size to its total exon length. The six pathways that scored significant (q value < 0.2; table 2) in the 2DNS test are highlighted by a black circle. Note that seemingly outlier gene sets may not reach significance due to their small size, which increases the variance of their distribution. For example, the Hormone ligand-binding receptors pathway (depicted in gray; H), has a high DN/DS ratio, but because of its small size (ten genes, 24 kb total exon length) its distribution is very widespread in the 2D space. (B–G) Null distributions for six significant (q < 0.2) pathways. (H) Null distribution for the Hormone ligand-binding receptors pathway as a typical example of a nonsignificant outlier. The observed positions of gene sets are indicated as orange dots highlighted by a black circle in the DN/DS–PN/PS plane, whereas the empirical distribution is shown as gray dots (N = 400,000). Light-orange dots show the scores of the jackknifed gene sets. The contour lines mark the proportion (0.5, 0.9, and 0.99) of the distribution that falls within these areas.
Mentions: Human single-nucleotide polymorphisms (SNPs) were inferred from the comparison of the whole genomes of 42 unrelated individuals sequenced by Complete Genomics (CG) at a depth of 51–89X coverage per genome (Drmanac et al. 2010). The 42 individuals were sampled in 3 African populations (four Luhya from Webuye, Kenya; four Maasai from Kinyawa, Kenya; and nine Yoruba from Ibadan, Nigeria), and 5 non-African populations (nine Utah residents with Northern and Western European ancestry from the CEPH collection; four Han Chinese from Beijing; four Gujarati Indians from Houston, TX; four Japanese from Tokyo; and four Toscans from Italy). The SNPs were divided into three categories: Sites which are polymorphic in Africans only (African SNPs), sites polymorphic in non-Africans only (non-African SNPs), and sites polymorphic in both Africans and non-Africans (shared SNPs). The shared SNPs presumably arose before the migration of modern humans out of Africa and are therefore depleted from recent deleterious mutations that otherwise could distort selective signals. This group of SNPs was used in the 2DNS test (fig. 1 and supplementary fig. S1, Supplementary Material online). The African and non-African SNPs were used in a further analysis to compare demographic patterns between the two regions (fig. 2).Fig. 1.—

Bottom Line: Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways.This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets.For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

View Article: PubMed Central - PubMed

Affiliation: CMPG, Institute of Ecology and Evolution, University of Berne, Switzerland Swiss Institute of Bioinformatics SIB, Lausanne, Switzerland Present address: Institute of Evolutionary Biology (UPF-CSIC), Barcelona, Spain josephine.daub@upf.edu laurent.excoffier@iee.unibe.ch.

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