Case Report: Exome Sequencing Identified Variants in Three Candidate Genes From Two Families With Hearing Loss, Onychodystrophy, and Epilepsy

A cohort of 542 individuals in 166 families with congenital hearing loss was recruited for whole-exome sequencing analysis. Here, we report the identification of three variants in five affected individuals in two unrelated families. In family 1, a nonsense mutation (c.1516C>T, p.R506*) in the ATP6V1B2 gene, a known causal allele for dominant deafness-onychodystrophy (DDOD), was identified in the mother and son with DDOD. However, a novel heterozygous variant (c.1590T>G, p.D530E) in TJP2, a known causal gene for hearing-loss, was also detected in the patients. In family 2, the same mutation (c.1516C>T, p.R506*) of ATP6V1B2 was detected from the father and daughter with DDOD. Furthermore, a novel heterozygous variant (c.733A>G, p.M245V) in the KIF11 gene was identified from the spouse with sensorineural hearing-loss and epilepsy. Notably, genotype-phenotype analysis of KIF11-associated disorders revealed that the p.M245V and two reported hearing-loss-associated variants (p.S235C and p.H244Y) are all mapped to a single β-sheet (Ser235∼M245) in the kinesin motor domain. Together, this is the first demonstration that ATP6V1B2-caused DDOD is an autosomal dominant genetic disease, compared to previous cases with de novo mutation. Our findings expand the variant spectrum of hearing-loss-associated genes and provide new insights on understanding of hearing-loss candidate genes ATP6V1B2, TJP2, and KIF11.

Estimation of Cry3Bb1 resistance allele frequency in field populations of western corn rootworm using a genetic marker

Following the discovery of western corn rootworm (WCR; Diabrotica virgifera virgifera) populations resistant to the Bacillus thuringiensis (Bt) protein Cry3Bb1, resistance was genetically mapped to a single locus on WCR chromosome 8 and linked SNP markers were shown to correlate with the frequency of resistance among field-collected populations from the US Corn Belt. The purpose of this paper is to further investigate the relationship between one of these resistance-linked markers and the causal resistance locus. Using data from laboratory bioassays and field experiments, we show that one allele of the resistance-linked marker increased in frequency in response to selection, but was not perfectly linked to the causal resistance allele. By coupling the response to selection data with a genetic model of the linkage between the marker and the causal allele, we developed a model that allowed marker allele frequencies to be mapped to causal allele frequencies. We then used this model to estimate the resistance allele frequency distribution in the US Corn Belt based on collections from 40 populations. These estimates suggest that chromosome 8 Cry3Bb1 resistance allele frequency was generally low (<10%) for 65% of the landscape, though an estimated 13% of landscape has relatively high (>25%) resistance allele frequency.

The support of genetic evidence for cardiovascular risk induced by antineoplastic drugs

Cardiovascular dysfunction is one of the most common complications of long-term cancer treatment. Growing evidence has shown that antineoplastic drugs can increase cardiovascular risk during cancer therapy, seriously affecting patient survival. However, little is known about the genetic factors associated with the cardiovascular risk of antineoplastic drugs. We established a compendium of genetic evidence that supports cardiovascular risk induced by antineoplastic drugs. Most of this genetic evidence is attributed to causal alleles altering the expression of cardiovascular disease genes. We found that antineoplastic drugs predicted to induce cardiovascular risk are significantly enriched in drugs associated with cardiovascular adverse reactions, including many first-line cancer treatments. Functional experiments validated that retinoid X receptor agonists can reduce triglyceride lipolysis, thus modulating cardiovascular risk. Our results establish a link between the causal allele of cardiovascular disease genes and the direction of pharmacological modulation, which could facilitate cancer drug discovery and clinical trial design.

Genetics and Epigenetics

Genetic influences on human disease can be understood in the context of essential and exacerbating causes. Alleles are essential causes when they are required for these diseases to occur. Severe diseases with essential genetic causes are rare unless they provide a compensating benefit in evolutionary fitness (accrued through increases in survival and/or reproduction) that offsets their fitness costs. Duchenne’s muscular dystrophy illustrates that upper limit of incidence for diseases that kill before reproduction and have essential genetic causes that provide no compensating benefit: about one death per 10,000 births. Sickle cell anaemia exceeds this limit in many populations because the causal allele confers a compensating benefit: protection against falciparum malaria. Alleles that contribute to common, severe diseases such as atherosclerosis and Alzheimer’s disease tend to be exacerbating causes, which act by increasing vulnerability to environmental causes. Inferring genetic causation from familial patterns is not straight-forward because genetic associations may be correlated with environmental exposures. Relatively high monozygotic twin cooncordances for schizophrenia, for example, are associated with in utero exposure to the parasite Toxoplasma gondii, which appears to cause a substantial portion of schizophrenia. Epigenetic contributions to disease involve relatively long-term but reversible modification of genetic influences that may occur in response to micro- or macroenvironmental exposures. Integration of these aspects of disease causation can be of practical use in the health sciences by clarifying interventions that can prevent, cure, or strongly ameliorate disease.

Rapid evolution of a skin-lightening allele in southern African KhoeSan

Skin pigmentation is under strong directional selection in northern European and Asian populations. The indigenous KhoeSan populations of far southern Africa have lighter skin than other sub-Saharan African populations, potentially reflecting local adaptation to a region of Africa with reduced UV radiation. Here, we demonstrate that a canonical Eurasian skin pigmentation gene, SLC24A5, was introduced to southern Africa via recent migration and experienced strong adaptive evolution in the KhoeSan. To reconstruct the evolution of skin pigmentation, we collected phenotypes from over 400 ≠Khomani San and Nama individuals and high-throughput sequenced candidate pigmentation genes. The derived causal allele in SLC24A5, p.Ala111Thr, significantly lightens basal skin pigmentation in the KhoeSan and explains 8 to 15% of phenotypic variance in these populations. The frequency of this allele (33 to 53%) is far greater than expected from colonial period European gene flow; however, the most common derived haplotype is identical among European, eastern African, and KhoeSan individuals. Using four-population demographic simulations with selection, we show that the allele was introduced into the KhoeSan only 2,000 y ago via a back-to-Africa migration and then experienced a selective sweep (s = 0.04 to 0.05 in ≠Khomani and Nama). The SLC24A5 locus is both a rare example of intense, ongoing adaptation in very recent human history, as well as an adaptive gene flow at a pigmentation locus in humans.

Genetic dissection of courtship song variation using the Drosophila Synthetic Population Resource

Connecting genetic variation to trait variation is a grand challenge in biology. Natural populations contain a vast reservoir of fascinating and potentially useful variation, but it is unclear if the causal alleles will generally have large enough effects for us to detect. Without knowing the effect sizes or allele frequency of typical variants, it is also unclear what methods will be most successful. Here, we use a multi-parent advanced intercross population (the Drosophila Synthetic Population Resource) to map natural variation in Drosophila courtship song traits. Most additive genetic variation in this population can be explained by a modest number of highly resolved QTL. Mapped QTL are universally multiallelic, suggesting that individual genes are "hotspots" of natural variation due to a small target size for major mutations and/or filtering of variation by positive or negative selection. Using quantitative complementation in randomized genetic backgrounds, we provide evidence that one causal allele is harbored in the gene Fhos, making this one of the few genes associated with behavioral variation in any taxon.