Genome-wide analysis of human hotspot intersected genes highlights the roles of meiotic recombination in evolution and disease

Tao Zhou,Jiahao Sha,Zuomin Zhou,Zhibin Hu,Xuejiang Guo

doi:10.1186/1471-2164-14-67

Abstract

BackgroundMeiotic recombination events are not randomly located, but rather cluster at hotspot regions. Recently, the fine-scale mapping of genome-wide human recombination hotspots was performed. Here, we systematically analyzed the evolutionary and disease-associated features of hotspots that overlapped with protein-coding genes.ResultsIn this study, we defined hotspot intersected genes as HI genes. We found that HI genes were prone to be located in the extracellular part and were functionally enriched in cell-to-cell communication. Tissue-specific genes and secreted protein encoding genes were overrepresented in HI genes, while housekeeping genes were underrepresented. Compared to slowly evolving housekeeping genes and random genes with lower recombination rates, HI genes evolved faster. The fact that brain and blood specific genes were overrepresented in HI genes indicates that they may be involved in the evolution of human intelligence and the immune system. We also found that genes related to disease were enriched in HI genes, especially genes with disease-associated chromosomal rearrangements. Hotspot sequence motifs were overrepresented in common sequences of HI genes and genes with disease-associated chromosomal rearrangements. We further listed repeat elements that were enriched both in hotspots and genes with disease-associated chromosomal rearrangements.ConclusionHI genes are evolving and may be involved in the generation of key features of human during evolution. Disease-associated genes may be by-products of meiotic recombination. In addition, hotspot sequence motifs and repeat elements showed the connection between meiotic recombination and genes with disease-associated chromosomal rearrangements at the sequence level. Our study will enable us to better understand the evolutionary and biological significance of human meiotic recombination.

Highlights

Meiotic recombination events are not randomly located, but rather cluster at hotspot regions
We focused on the consequences of human meiotic recombination hotspots, in regard to determining their effect on genome evolution, and evaluating their association with genome instability and diseases
Functional annotation of HI genes Gene Ontology analysis showed that HI gene products were prone to be located in the extracellular matrix, ion channel complex, plasma membrane part, and cell junctions (Figure 1; Table S1 in Additional file 1), indicating that HI genes may play an important role in cellto-cell cross-talk and the paracellular barrier

Summary

Introduction

Meiotic recombination events are not randomly located, but rather cluster at hotspot regions. We systematically analyzed the evolutionary and disease-associated features of hotspots that overlapped with proteincoding genes. Errors in meiotic recombination can cause genome of recombination rates and hotspots across the human genome [5]. Hotspot-associated sequence motifs have been reported in the human genome [6]. The PR domain zinc finger protein 9 (PRDM9) is thought to be a transregulator of meiotic recombination hotspots in humans and mice, and the hotspot sequence motifs may serve as binding sites for this protein [7]. The motifs of hotspot may drive genome instability, as they are found in disease-causing repeat sequences and breakpoint regions [8]. Since hotspots are not shared between humans and chimpanzees, hotspot sequences are thought to have evolved quickly [9]

Methods

Results

Conclusion