MCKAT: a multi-dimensional copy number variant kernel association test

Background Copy number variants (CNVs) are the gain or loss of DNA segments in the genome. Studies have shown that CNVs are linked to various disorders, including autism, intellectual disability, and schizophrenia. Consequently, the interest in studying a possible association of CNVs to specific disease traits is growing. However, due to the specific multi-dimensional characteristics of the CNVs, methods for testing the association between CNVs and the disease-related traits are still underdeveloped. We propose a novel multi-dimensional CNV kernel association test (MCKAT) in this paper. We aim to find significant associations between CNVs and disease-related traits using kernel-based methods. Results We address the multi-dimensionality in CNV characteristics. We first design a single pair CNV kernel, which contains three sub-kernels to summarize the similarity between two CNVs considering all CNV characteristics. Then, aggregate single pair CNV kernel to the whole chromosome CNV kernel, which summarizes the similarity between CNVs in two or more chromosomes. Finally, the association between the CNVs and disease-related traits is evaluated by comparing the similarity in the trait with kernel-based similarity using a score test in a random effect model. We apply MCKAT on genome-wide CNV datasets to examine the association between CNVs and disease-related traits, which demonstrates the potential usefulness the proposed method has for the CNV association tests. We compare the performance of MCKAT with CKAT, a uni-dimensional kernel method. Based on the results, MCKAT indicates stronger evidence, smaller p-value, in detecting significant associations between CNVs and disease-related traits in both rare and common CNV datasets. Conclusion A multi-dimensional copy number variant kernel association test can detect statistically significant associated CNV regions with any disease-related trait. MCKAT can provide biologists with CNV hot spots at the cytogenetic band level that CNVs on them may have a significant association with disease-related traits. Using MCKAT, biologists can narrow their investigation from the whole genome, including many genes and CNVs, to more specific cytogenetic bands that MCKAT identifies. Furthermore, MCKAT can help biologists detect significantly associated CNVs with disease-related traits across a patient group instead of examining each subject’s CNVs case by case.

Target of Rapamycin drives unequal responses to essential amino acid depletion in egg laying

Nutrition shapes a broad range of life history traits, ultimately impacting animal fitness. A key fitness-related trait, female fecundity is well known to change as a function of diet. In particular, the availability of dietary protein is one of the main drivers of egg production, and in the absence of essential amino acids egg laying declines. However, it is unclear whether all essential amino acids have the same impact on phenotypes like fecundity. Using a holidic diet, we fed adult female D. melanogaster diets that contain all necessary nutrients except one of the 10 essential amino acids and assessed the effects on egg production. For most essential amino acids, depleting a single amino acid induced as rapid a decline in egg production as when there were no amino acids in the diet. However, when either methionine or histidine were excluded from the diet, egg production declined more slowly. Next, we tested whether GCN2 and TOR were involved in this difference in response across amino acids. While mutations in GCN2 did not eliminate the differences in the rates of decline in egg laying among amino acid drop-out diets, we found that inhibiting TOR signalling caused egg laying to decline rapidly for all drop-out diets. TOR signalling does this by regulating the yolk-forming stages of egg chamber development. Our results suggest that amino acids differ in their ability to induce signalling via the TOR pathway. This is important because if phenotypes differ in sensitivity to individual amino acids, this generates the potential for mismatches between the output of a pathway and the animal's true nutritional status.

Human genetic analyses of organelles highlight the nucleus in age-related trait heritability

Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a 'hallmark' of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be 'haplosufficient', while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration.

GWAS meta-analysis reveals dual neuronal and immunological etiology for pain susceptibility

ABSTRACTChronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system and is coincident with a growing opioid crisis. While numerous genetic risk factors have been identified, its genetic basis remains poorly understood. Here, we conducted a meta-analysis of genome-wide association study (GWAS) summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, of which 62 have not been previously associated with a pain-related trait. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Two-sample Mendelian randomization indicated that depression, neuroticism, and immunological traits mediate many of these effects. These analyses double the number of known risk loci for pain susceptibility and support dual causation from neuronal and immunological genes, providing leads toward targets for novel pain medications.

Sex-specific ornament evolution is a consistent feature of climatic adaptation across space and time in dragonflies

Adaptation to different climates fuels the origins and maintenance of biodiversity. Detailing how organisms optimize fitness for their local climates is therefore an essential goal in biology. Although we increasingly understand how survival-related traits evolve as organisms adapt to climatic conditions, it is unclear whether organisms also optimize traits that coordinate mating between the sexes. Here, we show that dragonflies consistently adapt to warmer climates across space and time by evolving less male melanin ornamentation—a mating-related trait that also absorbs solar radiation and heats individuals above ambient temperatures. Continent-wide macroevolutionary analyses reveal that species inhabiting warmer climates evolve less male ornamentation. Community-science observations across 10 species indicate that populations adapt to warmer parts of species’ ranges through microevolution of smaller male ornaments. Observations from 2005 to 2019 detail that contemporary selective pressures oppose male ornaments in warmer years; and our climate-warming projections predict further decreases by 2070. Conversely, our analyses show that female ornamentation responds idiosyncratically to temperature across space and time, indicating the sexes evolve in different ways to meet the demands of the local climate. Overall, these macro- and microevolutionary findings demonstrate that organisms predictably optimize their mating-related traits for the climate just as they do their survival-related traits.

Evaluating yield and related trait of Haricot Bean varieties at Dambi Dollo University Research Site, Ethiopia

Haricot bean (Phaseolus vulagris L.) is an annual crop cultivated for food as it has high protein content. The objective of this study was to evaluate yield and yield-related traits of haricot bean varieties at the Dollo University research site. Five released and four local haricot bean varieties were used on 3 × 2 m (6 m2) experimental plots using randomized complete block design with three replications. Data pertaining to agronomic traits and yield performance of each variety were recorded and analyzed using R software version 4.0.5 and Microsoft Excel 2010. One way multivariate analysis showed a significant difference (p <0.05) in thousand seed weight. SAB-632, Local-4 (‘Burree’) and SAB-736 showed higher yield than the other haricot bean varieties. They are also high in all agronomic traits except SAB-736. Thousand seed weight and yield were high and significant with positively correlated to each other. Plant height had a high and significant positive correlation with the number of branches and seeds per plant. Generally, it is possible to say that haricot bean varieties, SAB-632 and Local-4(‘Burree’) are preferable in yield at the Dambi Dollo University research site according to the present findings. Therefore, it is good if these two haricot bean varieties are practised for multiplication at Dambi Dollo Research site and other related agro ecologies.

Asexual freshwater snails make poor mate choice decisions

Once-useful traits that no longer contribute to fitness tend to decay over time. We address whether the expression of mating-related traits that increase the fitness of sexually reproducing individuals but are likely less useful or even costly to asexual counterparts seems to exhibit decay in the latter. Potamopyrgus antipodarum is a New Zealand freshwater snail characterized by repeated transitions from sexual to asexual reproduction. The frequent coexistence of sexual and asexual lineages makes P. antipodarum an excellent model for the study of mating-related trait loss. We used a mating choice assay including sexual and asexual P. antipodarum females and conspecific (presumed better choice) vs. heterospecific (presumed worse choice) males to evaluate the loss of behavioural traits related to sexual reproduction. We found that sexual females engaged in mating behaviours with conspecific mating partners more frequently and for a greater duration than with heterospecific mating partners, while asexual females seemed to lack the ability to make a choice. These results suggest that selection acting to maintain mate choice in asexual P. antipodarum is weak or ineffective relative to sexual females and that asexual reproduction likely contributes to the evolutionary decay of behavioural traits in this system.

A cluster of Ankyrin and Ankyrin-TPR repeat genes is associated with panicle branching diversity in rice

The number of grains per panicle is an important yield-related trait in cereals which depends in part on panicle branching complexity. One component of this complexity is the number of secondary branches per panicle. Previously, a GWAS site associated with secondary branch and spikelet numbers per panicle in rice was identified. Here we combined gene capture, bi-parental genetic population analysis, expression profiling and transgenic approaches in order to investigate the functional significance of a cluster of 6 ANK and ANK-TPR genes within the QTL. Four of the ANK and ANK-TPR genes present a differential expression associated with panicle secondary branch number in contrasted accessions. These differential expression patterns correlate in the different alleles of these genes with specific deletions of potential cis-regulatory sequences in their promoters. Two of these genes were confirmed through functional analysis as playing a role in the control of panicle architecture. Our findings indicate that secondary branching diversity in the rice panicle is governed in part by differentially expressed genes within this cluster encoding ANK and ANK-TPR domain proteins that may act as positive or negative regulators of panicle meristem’s identity transition from indeterminate to determinate state.

MCKAT, a multi-dimensional copy number variant kernel association test

BackgroundCopy number variants (CNVs) are the gain or loss of DNA segments in the genome. Studies have shown that CNVs are linked to various disorders, including autism, intellectual disability, and schizophrenia.Consequently, the interest in studying a possible association of CNVs to specific disease traits is growing. However, due to the specific multi-dimensional characteristics of the CNVs, methods for testing the association between CNVs and the disease-related traits are still underdeveloped. We propose a novel multi-dimensional CNV kernel association test (MCKAT) in this paper. We aim to find significant associations between CNVs and disease-related traits using kernel-based methods.ResultsWe address the multi-dimensionality in CNV characteristics. We first design a single pair CNV kernel, which contains three sub-kernels to summarize the similarity between two CNVs considering all CNV characteristics. Then, aggregate single pair CNV kernel to the whole chromosome CNV kernel, which summarizes the similarity between CNVs in two or more chromosomes. Finally, the association between the CNVs and disease-related traits is evaluated by comparing the similarity in the trait with kernel-based similarity using a score test in a random effect model. We apply MCKAT on genome-wide CNV datasets to examine the association between CNVs and disease-related traits, which demonstrates the potential usefulness the proposed method has for the CNV association tests. We compare the performance of MCKAT with CKAT, a uni-dimensional kernel method. Based on the results, MCKAT indicates stronger evidence, smaller p-value, in detecting significant associations between CNVs and disease-related traits in both rare and common CNV datasets.ConclusionA multi-dimensional copy number variant kernel association test can detect significantly associated CNVs with any disease-related trait. MCKAT can help biologists detect significantly associated CNVs with any disease-related trait across a patient group instead of examining the CNVs case by case in each subject.