Interlocus gene conversion events introduce deleterious mutations into at least 1% of human genes associated with inherited disease

Abstract

Establishing the molecular basis of DNA mutations that cause inherited disease is of fundamental importance to understanding the origin, nature, and clinical sequelae of genetic disorders in humans. The majority of disease-associated mutations constitute single-base substitutions and short deletions and/or insertions resulting from DNA replication errors and the repair of damaged bases. However, pathological mutations can also be introduced by nonreciprocal recombination events between paralogous sequences, a phenomenon known as interlocus gene conversion (IGC). IGC events have thus far been linked to pathology in more than 20 human genes. However, the large number of duplicated gene sequences in the human genome implies that many more disease-associated mutations could originate via IGC. Here, we have used a genome-wide computational approach to identify disease-associated mutations derived from IGC events. Our approach revealed hundreds of known pathological mutations that could have been caused by IGC. Further, we identified several dozen high-confidence cases of inherited disease mutations resulting from IGC in ∼1% of all genes analyzed. About half of the donor sequences associated with such mutations are functional paralogous genes, suggesting that epistatic interactions or differential expression patterns will determine the impact upon fitness of specific substitutions between duplicated genes. In addition, we identified thousands of hitherto undescribed and potentially deleterious mutations that could arise via IGC. Our findings reveal the extent of the impact of interlocus gene conversion upon the spectrum of human inherited disease.

Figure 1.

Interlocus gene conversion (IGC) from the human processed pseudogene GJA1P1 to its functional paralog, GJA1. The chromosomal locations of GJA1 and GJA1P1 are 6q22.31 and 5q21.3, respectively. The filled black box in GJA1 represents the coding sequence, whereas the empty boxes denote the 5′UTR and 3′UTR. The light-gray shadings connect regions of similarity between the two sequences and serve to highlight the absence of intron 1 in the pseudogene. Regions representing the minimal conversion tract are connected by dark gray shading. The sequence in these regions is identical between the GJA1 disease allele and GJA1P1. A second, independent IGC event between the two paralogous sequences is not shown here.

Figure 2.

Excess of interlocus gene conversion (IGC) between intrachromosomal paralogous sequences. HGMD genes with IGC: 30 genes with deleterious mutations introduced by IGC. All HGMD genes: 3196 genes from the HGMD database.

Figure 3.

Distance in kilobases (kb) between donor and acceptor sequences for the 25 intrachromosomal IGC pairs with assigned donor sequences.

Figure 4.

Interlocus gene conversion from FCGR3B to FCGR3A. The FCGR3A gene encodes a receptor for the Fc portion of immunoglobulin G, which is involved in the removal of antigen–antibody complexes from the circulation. The highly similar paralog, FCGR3B, which resides only 73 kb downstream from FCGR3A, encodes a shorter protein due to differences in the positions of both the start and stop codons. Coding exons are shown as filled boxes, UTRs as empty boxes. Introns are represented as lines and are not drawn to scale. The black asterisks indicate the normal stop codons of the FCGR3A and FCGR3B genes; the gray asterisk identifies the premature stop codon in the FCGR3A gene that is introduced by an IGC event with FCGR3B.