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Early evolutionary history and genomic features of gene duplicates in the human genome.

Bu L, Katju V - BMC Genomics (2015)

Bottom Line: Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions.The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric).The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of New Mexico, Albuquerque, NM, 87131, USA. lijing@unm.edu.

ABSTRACT

Background: Human gene duplicates have been the focus of intense research since the development of array-based and targeted next-generation sequencing approaches in the last decade. These studies have primarily concentrated on determining the extant copy-number variation from a population-genomic perspective but lack a robust evolutionary framework to elucidate the early structural and genomic characteristics of gene duplicates at emergence and their subsequent evolution with increasing age.

Results: We analyzed 184 gene duplicate pairs comprising small gene families in the draft human genome with 10% or less synonymous sequence divergence. Human gene duplicates primarily originate from DNA-mediated events, taking up genomic residence as intrachromosomal copies in direct or inverse orientation. The distribution of paralogs on autosomes follows random expectations in contrast to their significant enrichment on the sex chromosomes. Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions. Surprisingly, despite the large average length of human genes, the majority of extant duplicates (83%) are complete duplicates, wherein the entire ORF of the ancestral copy was duplicated. The preponderance of complete duplicates is in accord with an extremely large median duplication span of 36 kb, which enhances the probability of capturing ancestral ORFs in their entirety. With increasing evolutionary age, human paralogs exhibit declines in (i) the frequency of intrachromosomal paralogs, and (ii) the proportion of complete duplicates. These changes may reflect lower survival rates of certain classes of duplicates and/or the role of purifying selection. Duplications arising from RNA-mediated events comprise a small fraction (11.4%) of all human paralogs and are more numerous in older evolutionary cohorts of duplicates.

Conclusions: The degree of structural resemblance, genomic location and duplication span appear to influence the long-term maintenance of paralogs in the human genome. The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric). The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.

No MeSH data available.


Related in: MedlinePlus

Composition frequencies of intra- and interchromosomal duplication within three age-cohorts of human gene duplicate pairs. The sample sizes of duplicate pairs within each age category (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1) are provided above the corresponding bars. The total sample size comprised 172 duplicate pairs with assigned chromosomal locations for both paralogs. Chromosomal location is significantly associated with the KS values for paralogs (G = 25.1, p = 3.59 × 10−6)
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Fig2: Composition frequencies of intra- and interchromosomal duplication within three age-cohorts of human gene duplicate pairs. The sample sizes of duplicate pairs within each age category (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1) are provided above the corresponding bars. The total sample size comprised 172 duplicate pairs with assigned chromosomal locations for both paralogs. Chromosomal location is significantly associated with the KS values for paralogs (G = 25.1, p = 3.59 × 10−6)

Mentions: With respect to chromosomal location, 83 % (143/172) of the entire data set of 172 gene duplicate pairs comprise intrachromosomal duplications with both paralogs residing on the same chromosome; the remaining 17 % (29/172) pairs display interchromosomal location of the two paralogs (Fig. 2). The exclusion of 26 duplicate pairs exhibiting gene conversion resulted in 82 % (121/148) intrachromosomal and 18 % (27/148) interchromosomal duplications, respectively. We further investigated whether the relative frequencies of intrachromosomal vs. interchromosomal duplicates was altered with increasing evolutionary age by classifying the human duplicate pairs into three evolutionary age-cohorts (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1). Although intrachromosomal duplicates dominate in frequency within each of the three age-cohorts, a clear decline in the frequency of intrachromosomal duplicates (and increase in the frequency of interchromosomal duplicates) is apparent as a function of increasing synonymous divergence: 100 (39/39), 88 (65/74), and 66 % (39/59) from evolutionarily younger to older age-cohorts (Fig. 2). A G-test of independence revealed chromosomal location to be significantly associated with synonymous divergence between paralogs (G = 25.1, df = 2, p = 3.59 × 10−6). This significant trend of frequency decline of intrachromosomal duplicates with increasing evolutionary age remains unaltered even when the 26 duplicates pairs with signatures of gene conversion are excluded from the analyses (G = 23.2, df = 2, p = 9.35× 10−6). RNA-mediated gene duplicates appear to be older on average (higher KS) and more likely to be found on different chromosomes. These biases in the features of RNA-mediated duplications may be responsible for the apparent relationship between chromosomal location (intra- vs. interchromosomal) and evolutionary age (KS). However, when 21 putative RNA-mediated gene duplicate pairs were excluded from the analysis, we still found a significant increase in the proportion of interchromosomal duplicates with evolutionary age (G =10.2, df = 2, p = 0.006).Fig. 2


Early evolutionary history and genomic features of gene duplicates in the human genome.

Bu L, Katju V - BMC Genomics (2015)

Composition frequencies of intra- and interchromosomal duplication within three age-cohorts of human gene duplicate pairs. The sample sizes of duplicate pairs within each age category (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1) are provided above the corresponding bars. The total sample size comprised 172 duplicate pairs with assigned chromosomal locations for both paralogs. Chromosomal location is significantly associated with the KS values for paralogs (G = 25.1, p = 3.59 × 10−6)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4546093&req=5

Fig2: Composition frequencies of intra- and interchromosomal duplication within three age-cohorts of human gene duplicate pairs. The sample sizes of duplicate pairs within each age category (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1) are provided above the corresponding bars. The total sample size comprised 172 duplicate pairs with assigned chromosomal locations for both paralogs. Chromosomal location is significantly associated with the KS values for paralogs (G = 25.1, p = 3.59 × 10−6)
Mentions: With respect to chromosomal location, 83 % (143/172) of the entire data set of 172 gene duplicate pairs comprise intrachromosomal duplications with both paralogs residing on the same chromosome; the remaining 17 % (29/172) pairs display interchromosomal location of the two paralogs (Fig. 2). The exclusion of 26 duplicate pairs exhibiting gene conversion resulted in 82 % (121/148) intrachromosomal and 18 % (27/148) interchromosomal duplications, respectively. We further investigated whether the relative frequencies of intrachromosomal vs. interchromosomal duplicates was altered with increasing evolutionary age by classifying the human duplicate pairs into three evolutionary age-cohorts (KS = 0, 0 < KS ≤ 0.025, and 0.025 < KS ≤ 0.1). Although intrachromosomal duplicates dominate in frequency within each of the three age-cohorts, a clear decline in the frequency of intrachromosomal duplicates (and increase in the frequency of interchromosomal duplicates) is apparent as a function of increasing synonymous divergence: 100 (39/39), 88 (65/74), and 66 % (39/59) from evolutionarily younger to older age-cohorts (Fig. 2). A G-test of independence revealed chromosomal location to be significantly associated with synonymous divergence between paralogs (G = 25.1, df = 2, p = 3.59 × 10−6). This significant trend of frequency decline of intrachromosomal duplicates with increasing evolutionary age remains unaltered even when the 26 duplicates pairs with signatures of gene conversion are excluded from the analyses (G = 23.2, df = 2, p = 9.35× 10−6). RNA-mediated gene duplicates appear to be older on average (higher KS) and more likely to be found on different chromosomes. These biases in the features of RNA-mediated duplications may be responsible for the apparent relationship between chromosomal location (intra- vs. interchromosomal) and evolutionary age (KS). However, when 21 putative RNA-mediated gene duplicate pairs were excluded from the analysis, we still found a significant increase in the proportion of interchromosomal duplicates with evolutionary age (G =10.2, df = 2, p = 0.006).Fig. 2

Bottom Line: Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions.The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric).The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of New Mexico, Albuquerque, NM, 87131, USA. lijing@unm.edu.

ABSTRACT

Background: Human gene duplicates have been the focus of intense research since the development of array-based and targeted next-generation sequencing approaches in the last decade. These studies have primarily concentrated on determining the extant copy-number variation from a population-genomic perspective but lack a robust evolutionary framework to elucidate the early structural and genomic characteristics of gene duplicates at emergence and their subsequent evolution with increasing age.

Results: We analyzed 184 gene duplicate pairs comprising small gene families in the draft human genome with 10% or less synonymous sequence divergence. Human gene duplicates primarily originate from DNA-mediated events, taking up genomic residence as intrachromosomal copies in direct or inverse orientation. The distribution of paralogs on autosomes follows random expectations in contrast to their significant enrichment on the sex chromosomes. Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions. Surprisingly, despite the large average length of human genes, the majority of extant duplicates (83%) are complete duplicates, wherein the entire ORF of the ancestral copy was duplicated. The preponderance of complete duplicates is in accord with an extremely large median duplication span of 36 kb, which enhances the probability of capturing ancestral ORFs in their entirety. With increasing evolutionary age, human paralogs exhibit declines in (i) the frequency of intrachromosomal paralogs, and (ii) the proportion of complete duplicates. These changes may reflect lower survival rates of certain classes of duplicates and/or the role of purifying selection. Duplications arising from RNA-mediated events comprise a small fraction (11.4%) of all human paralogs and are more numerous in older evolutionary cohorts of duplicates.

Conclusions: The degree of structural resemblance, genomic location and duplication span appear to influence the long-term maintenance of paralogs in the human genome. The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric). The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.

No MeSH data available.


Related in: MedlinePlus