Abstract
Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases—about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles.
Highlights
Genomic instability is a major contributor to de novo mutations that can occur in the process of human genome evolution [1,2,3]
Genomic instability due to the intrinsic sequence architecture of the genome, such as low copy repeats (LCRs), is a major contributor to de novo mutations that can occur in the process of human genome evolution
LCRs can mediate genomic rearrangements associated with genomic disorders by acting as substrates for nonallelic homologous recombination
Summary
Genomic instability is a major contributor to de novo mutations that can occur in the process of human genome evolution [1,2,3]. Low copy repeat (LCR) mediated NAHR plays a significant role in genomic instability resulting in rearrangements associated with genomic disorders [5]. LCRs, known as segmental duplications, are two or more repeated sequences that usually span 10–400 kilobases (kb) each and share >95% DNA sequence identity [6,7]. LCRs are highly homologous, and constitute ~5–10% of the human and great ape genomes [6,8,9]. LCRs provide substrates for NAHR-mediated crossing-over that results in structural variants (SVs) including copy number variants (CNVs) such as duplications and deletions of large genomic segments [5] or copy number neutral events such as inversions [10,11,12]
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