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

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.

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.

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.