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Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

ABSTRACT: The expansion of DUF1220 domain copy number during human evolution is a dramatic example of rapid and repeated domain duplication. Although patterns of expression, homology, and disease associations suggest a role in cortical development, this hypothesis has not been robustly tested using phylogenetic methods. Here, we estimate DUF1220 domain counts across 12 primate genomes using a nucleotide Hidden Markov Model. We then test a series of hypotheses designed to examine the potential evolutionary significance of DUF1220 copy number expansion. Our results suggest a robust association with brain size, and more specifically neocortex volume. In contradiction to previous hypotheses, we find a strong association with postnatal brain development but not with prenatal brain development. Our results provide further evidence of a conserved association between specific loci and brain size across primates, suggesting that human brain evolution may have occurred through a continuation of existing processes.

SUBMITTER: Zimmer F

PROVIDER: S-EPMC4558844 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

Zimmer Fabian F Montgomery Stephen H SH

Genome biology and evolution 20150625 8

The expansion of DUF1220 domain copy number during human evolution is a dramatic example of rapid and repeated domain duplication. Although patterns of expression, homology, and disease associations suggest a role in cortical development, this hypothesis has not been robustly tested using phylogenetic methods. Here, we estimate DUF1220 domain counts across 12 primate genomes using a nucleotide Hidden Markov Model. We then test a series of hypotheses designed to examine the potential evolutionary ...[more]

PMID: 26112965

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Project description:BackgroundDUF1220 protein domains found primarily in Neuroblastoma BreakPoint Family (NBPF) genes show the greatest human lineage-specific increase in copy number of any coding region in the genome. There are 302 haploid copies of DUF1220 in hg38 (~160 of which are human-specific) and the majority of these can be divided into 6 different subtypes (referred to as clades). Copy number changes of specific DUF1220 clades have been associated in a dose-dependent manner with brain size variation (both evolutionarily and within the human population), cognitive aptitude, autism severity, and schizophrenia severity. However, no published methods can directly measure copies of DUF1220 with high accuracy and no method can distinguish between domains within a clade.ResultsHere we describe a novel method for measuring copies of DUF1220 domains and the NBPF genes in which they are found from whole genome sequence data. We have characterized the effect that various sequencing and alignment parameters and strategies have on the accuracy and precision of the method and defined the parameters that lead to optimal DUF1220 copy number measurement and resolution. We show that copy number estimates obtained using our read depth approach are highly correlated with those generated by ddPCR for three representative DUF1220 clades. By simulation, we demonstrate that our method provides sufficient resolution to analyze DUF1220 copy number variation at three levels: (1) DUF1220 clade copy number within individual genes and groups of genes (gene-specific clade groups) (2) genome wide DUF1220 clade copies and (3) gene copy number for DUF1220-encoding genes.ConclusionsTo our knowledge, this is the first method to accurately measure copies of all six DUF1220 clades and the first method to provide gene specific resolution of these clades. This allows one to discriminate among the ~300 haploid human DUF1220 copies to an extent not possible with any other method. The result is a greatly enhanced capability to analyze the role that these sequences play in human variation and disease.

Dataset Information

Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

Publications

Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion.

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