Stephenson, J. | bioRxiv Science

bioRxiv2018

Identification of a genetic element required for spore killing in Neurospora

Meiotic drive elements like Spore killer-2 (Sk-2) in Neurospora are transmitted through sexual reproduction to the next generation in a biased manner. Sk-2 achieves this biased transmission through spore killing. Here, we identify rfk-1 as a gene required for the spore killing mechanism. The rfk-1 gene is associated with a 1,481 bp DNA interval (called AH36) near the right border of the 30 cM Sk-2 element, and its deletion eliminates the ability of Sk-2 to kill spores. The rfk-1 gene also appears to be sufficient for spore killing because its insertion into a non-Sk-2 isolate disrupts sexual reproduction after the initiation of meiosis. Although the complete rfk-1 transcript has yet to be defined, our data indicate that rfk-1 encodes a protein of at least 39 amino acids and that rfk-1 has evolved from a partial duplication of gene ncu07086. We also present evidence that rfk-1s location near the right border of Sk-2 is critical for the success of spore killing. Increasing the distance of rfk-1 from the right border of Sk-2 causes it to be inactivated by a genome defense process called meiotic silencing by unpaired DNA (MSUD), adding to accumulating evidence that MSUD exists, at least in part, to protect genomes from meiotic drive.

genetics↗

bioRxiv2017

Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

genetics↗