Large multiallelic copy number variations in humans

Area of Science:

• Genomics
• Human Genetics
• Population Genetics

Background:

• Genomic segments vary widely in copy number across human genomes.
• Understanding copy number variations (CNVs) is crucial for comprehending human genetic diversity and its impact on gene dosage.

Purpose of the Study:

• To develop methods for identifying copy numbers, alleles, and haplotypes at large multiallelic CNVs (mCNVs) using whole-genome sequence data.
• To quantify the contribution of mCNVs to human gene dosage variation and gene expression.

Main Methods:

• Analysis of 849 genomes from the 1000 Genomes Project.
• Identification of large ( >5-kb) mCNVs, including duplications with multiple segregating alleles.
• Development of initial strategies for mCNV analysis via imputation.

Main Results:

• Identification of most large mCNVs, including 3,878 duplications, with 1,356 having 3 or more segregating alleles.
• mCNVs account for the majority of human gene dosage variation, exceeding deletions and biallelic duplications sevenfold.
• Discovery of 'runaway duplication haplotypes' for genes like HPR and ORM1.

Conclusions:

• mCNVs are a major source of human genetic variation influencing gene dosage and expression.
• The study provides a foundational dataset and analytical approaches for studying mCNVs.
• Further research into mCNVs and their functional consequences is warranted.