
兄弟の形質値を利用することで、複雑形質の遺伝子構造、特に極端な形質値を示す個体の遺伝子構造を推定できる。


coremsg

The use of siblings to infer the factors influencing complex traits has been a cornerstone of quantitative genetics. Here we utilise siblings for a novel application: the inference of genetic architecture, specifically that relating to individuals with extreme trait values (e.g. in the top 1%). Inferring the genetic architecture most relevant to this group of individuals is important because they are at greatest risk of disease and may be more likely to harbour rare variants of large effect due to natural selection. We develop a theoretical framework that derives expected distributions of sibling trait values based on an index sibling’s trait value, estimated trait heritability, and null assumptions that include infinitesimal genetic effects and environmental factors that are either controlled for or have combined Gaussian effects. This framework is then used to develop statistical tests powered to distinguish between trait tails characterised by common polygenic architecture from those that include substantial enrichments of de novo or rare variant (Mendelian) architecture. We apply our tests to UK Biobank data here, although we note that they can be used to infer genetic architecture in any cohort or health registry that includes siblings and their trait values, since these tests do not use genetic data. We describe how our approach has the potential to help disentangle the genetic and environmental causes of extreme trait values, and to improve the design and power of future sequencing studies to detect rare variants.

### Competing Interest Statement

The authors have declared no competing interest.

Sibling Similarity Can Reveal Key Insights into Genetic Architecture

遺伝子構造の洞察を明らかにする兄弟の類似性

title_rewrite


Khdc3の変異は、その遺伝子型に関係なく、マウスの肝臓の代謝遺伝子発現を変化させ、その影響が複数世代にわたって持続する。この現象は、生殖細胞の小RNAの異常発現が原因と考えられる。


Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell gene Khdc3 have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended from Khdc3 mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes of Khdc3 -null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes, potentially indefinitely.

### Competing Interest Statement

The authors have declared no competing interest.

Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner

遺伝子変異の影響が世代を超えて持続する-khdc3の変異がマウスの代謝を変化させる


遺伝子変異の影響が世代を超えて持続する: Khdc3の変異がマウスの代謝を変化させる



マウスにおいて、非伝達的な父性アレルによるトランスジェネレーショナルな遺伝的効果は極めて稀であり、自然発生的な遺伝的変異の下では、表現型の変異に大きく寄与しないと結論付けられる。


Transgenerational genetic effects are defined as the effects of untransmitted parental alleles on the phenotype of their offspring. Well-known transgenerational genetic effects, in humans and other mammals, are the effects of a parental genotype on the nurturing ability of the parents, coined “genetic nurture”. However, there exist examples of transgenerational genetic effects in model organisms that are independent of nurturing effects and support the epigenetic transmission of a memory of the parental genotype possibly mediated by small RNA species. To test whether such transgenerational epigenetic effects might exist in mammals, we generated 833 isogenic C57BL/6J (B6) mice that differed only by the presence in the genome of their sire of one copy of four A/J chromosomes (MMU 15, 17, 19 or X). We measured 25 anatomical traits and performed RNA-Seq on five distinct tissues (heart, liver, pituitary, whole embryo, and placenta). There was no evidence of a significant effect from untransmitted A/J sire chromosome alleles, whether on anatomical traits or gene expression level. We observed an effect on Mid1 expression levels in multiple tissues, but this was shown to be due to a de novo mutation that occurred in one of the sire lines. We conclude that transgenerational epigenetic memory of non-transmitted paternal alleles - if it exists - is uncommon in mice and likely other mammals.

### Competing Interest Statement

The authors have declared no competing interest.

Lack of evidence supporting transgenerational effects of non-transmitted paternal alleles on the murine transcriptome

マウスの非伝達的な父性アレルがトランスジェネレーショナルな転写産物に及ぼす影響を支持する証拠の欠如