Abstract
The human amylase gene cluster includes the human salivary (AMY1) and pancreatic amylase genes (AMY2A and AMY2B), and is a highly variable and dynamic region of the genome. Copy number variation (CNV) of AMY1 has been implicated in human dietary adaptation, and in population association with obesity, but neither of these findings has been independently replicated. Despite these functional implications, the structural genomic basis of CNV has only been defined in detail very recently. In this work, we use high-resolution analysis of copy number, and analysis of segregation in trios, to define new, independent allelic series of amylase CNVs in sub-Saharan Africans, including a series of higher-order expansions of a unit consisting of one copy each of AMY1, AMY2A, and AMY2B. We use fiber-FISH (fluorescence in situ hybridization) to define unexpected complexity in the accompanying rearrangements. These findings demonstrate recurrent involvement of the amylase gene region in genomic instability, involving at least five independent rearrangements of the pancreatic amylase genes (AMY2A and AMY2B). Structural features shared by fundamentally distinct lineages strongly suggest that the common ancestral state for the human amylase cluster contained more than one, and probably three, copies of AMY1.
Highlights
The adoption of agriculture was one of the most radical and pervasive innovations among the many changes introduced by humans to their own environments
Comparison of amylase copy number with flanking SNP haplotypes suggests that this (AMY1)4(AMY2A)2(AMY2B)1 haplotype (AMY2B_012211) is the commonest type of (AMY2A)2(AMY2B)1 structure, whereas we found no evidence for other alleles corresponding to the longer (AMY1)8(AMY2A)2(AMY2B)1 haplotype (AMY2B_012341) in NA19119
Our work shows that pancreatic amylase (AMY2A/2B) genes appear to have undergone at least five independent rearrangements to create new copy numbers in humans since the split from chimpanzees
Summary
The adoption of agriculture was one of the most radical and pervasive innovations among the many changes introduced by humans to their own environments. Starch is initially digested by the enzyme amylase, present in humans in two tissue-specific isoenzymes: salivary amylase, encoded by the gene AMY1, and pancreatic amylase, encoded by AMY2A and AMY2B. 1, and early observations on pedigree segregation of protein electrophoretic variants demonstrated common and extensive copy number variation (CNV) in the salivary amylase gene AMY1 [Pronk and Frants, 1979; Pronk et al, 1982] These observations, coupled with detailed mapping of cloned genomic sequences, showed that there were common haplotypes containing odd numbers of AMY1 genes, differing by pairs of genes in inverted orientation [Bank et al, 1992; Groot et al., 1989; Groot et al, 1991; Groot et al, 1990]. Higher-resolution studies of the variation have demonstrated that most humans have an even number of AMY1 copies, as predicted by the predominance of haplotypes containing odd numbers, with an overall copy number range of 2 to 18 copies per individual [Carpenter et al, 2015; Usher et al, 2015]
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