
형제 데이터를 활용하여 복잡형질의 유전적 구조, 특히 극단값 집단에서의 유전적 구조를 추론할 수 있다.


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

유전적-구조-파악을-위한-형제-유사성의-활용


유전적 구조 파악을 위한 형제 유사성의 활용


title_rewrite


인구 기반 BRCA 검사는 가족력 기반 검사보다 더 많은 유방암과 난소암을 예방할 수 있으며, 비용 효과적이다.


In a Markov model, testing all women in Canada for BRCA1 and 2 genetic mutations was cost-effective, compared with testing only women with a family history of breast cancer.

Is Population-Based BRCA Testing Cost-Effective?

모든-여성을-대상으로-한-brca-검사가-비용-효과적인가-


모든 여성을 대상으로 한 BRCA 검사가 비용 효과적인가?



난소 노화와 암 위험, 그리고 신규 돌연변이 발생률 간에 유전적 연관성이 있다.


Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes.

Genetic links between ovarian ageing, cancer risk and de novo mutation rates - Nature

난소-노화-암-위험-및-신규-돌연변이-발생률-간의-유전적-연관성


난소 노화, 암 위험 및 신규 돌연변이 발생률 간의 유전적 연관성



아버지의 Trim66 결핍이 자손의 출생 시 체중 증가를 유발한다.


The tripartite motif-containing protein 66 (TRIM66, also known as TIF1-delta) is a PHD-Bromo containing protein primarily expressed in post-meiotic male germ cells known as spermatids. Biophysical assays showed that TRIM66 PHD-Bromo domain binds to H3 N-terminus only when lysine 4 is unmethylated. We addressed TRIM66’s role in reproduction by loss-of-function genetics in the mouse. Males homozygous for Trim66-null mutations produced functional spermatozoa. Round spermatids lacking TRIM66 upregulated a network of genes involved in histone acetylation and H3K4 methylation. Profiling of H3K4me3 patterns in the sperm produced by Trim66 -null mutant showed minor alterations below statistical significance. Unexpectedly, Trim66 -null males, but not females, sired pups overweight at birth, hence revealing that Trim66 mutations cause a paternal effect phenotype.

### Competing Interest Statement

The authors have declared no competing interest.

Trim66’s paternal deficiency causes intrauterine overgrowth

아버지의-trim66-결핍이-자궁-내-과성장을-유발한다


아버지의 Trim66 결핍이 자궁 내 과성장을 유발한다



미토콘드리아 DNA 하플로그룹 명명법의 복잡성과 비표준화로 인해 유전 데이터 분석 및 해석에 편향이 발생할 수 있다.


Population-based studies of human mitochondrial genetic diversity often require the classification of mitochondrial DNA (mtDNA) haplotypes into more than 5400 described haplogroups, and further grouping those into hierarchically higher haplogroups. Such secondary haplogroup groupings (e.g., “macro-haplogroups”) vary across studies, as they depend on the sample quality, technical factors of haplogroup calling, the aims of the study, and the researchers’ understanding of the mtDNA haplogroup nomenclature. Retention of historical nomenclature coupled with a growing number of newly described mtDNA lineages results in increasingly complex and inconsistent nomenclature that does not reflect phylogeny well. This “clutter” leaves room for grouping errors and inconsistencies across scientific publications, especially when the haplogroup names are used as a proxy for secondary groupings, and represents a source for scientific misinterpretation.

Here we explore the effects of phylogenetically insensitive secondary mtDNA haplogroup groupings, and the lack of standardized secondary haplogroup groupings on downstream analyses and interpretation of genetic data. We demonstrate that frequency-based analyses produce inconsistent results when different secondary mtDNA groupings are applied, and thus allow for vastly different interpretations of the same genetic data. The lack of guidelines and recommendations on how to choose appropriate secondary haplogroup groupings presents an issue for the interpretation of results, as well as their comparison and reproducibility across studies.

To reduce biases originating from arbitrarily defined secondary nomenclature-based groupings, we suggest that future updates of mtDNA phylogenies aimed for the use in mtDNA haplogroup nomenclature should also provide well-defined and standardized sets of phylogenetically meaningful algorithm-based secondary haplogroup groupings such as “macro-haplogroups”, “meso-haplogroups”, and “micro-haplogroups”. Ideally, each of the secondary haplogroup grouping levels should be informative about different human population history events. Those phylogenetically informative levels of haplogroup groupings can be easily defined using TreeCluster , and then implemented into haplogroup callers such as HaploGrep3 . This would foster reproducibility across studies, provide a grouping standard for population-based studies, and reduce errors associated with haplogroup nomenclatures in future studies.

### Competing Interest Statement

The authors have declared no competing interest.

*   NBG
    :   Nomenclature-Based Groupings
    SC
    :   Single Character grouping
    SCL
    :   Single Character and L with one digit grouping
    ABG
    :   Algorithm-Based Groupings
    mtDNA
    :   Mitochondrial DNA
    rCRS
    :   The revised Cambridge Reference Sequence
    RSRS
    :   The Reconstructed Sapiens Reference Sequence
    MDS
    :   Multidimensional scaling
    CA
    :   Correspondence analysis
    rhb_01 
    :   Results of rhierBAPS level 1
    rhb_02 
    :   Results of rhierBAPS level 2
    rhb_03 
    :   Results of rhierBAPS level 3
    tc_0.006 
    :   Results of TreeCluster with the threshold value of 0.006
    tc_0.005 
    :   Results of TreeCluster with the threshold value of 0.005
    tc_0.004 
    :   Results of TreeCluster with the threshold value of 0.004
    tc_0.003 
    :   Results of TreeCluster with the threshold value of 0.003

*   ACB
    :   African Caribbean in Barbados
    ASW
    :   African Ancestry in SW USA
    MSL
    :   Mende in Sierra Leone
    GWD
    :   Gambian in Western Division – Mandinka
    ESN
    :   Esan in Nigeria
    YRI
    :   Yoruba in Ibadan, Nigeria
    LWK
    :   Luhya in Webuye, Kenya

mtDNA “Nomenclutter” and its Consequences on the Interpretation of Genetic Data

미토콘드리아-dna-명명-혼란-과-유전-데이터-해석에-미치는-영향


미토콘드리아 DNA "명명 혼란"과 유전 데이터 해석에 미치는 영향



DNAH3 결핍은 정자 편모의 내부 다이닌 팔 구조 및 기능 장애를 유발하여 남성 불임을 초래한다.


Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients’ sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

### Competing Interest Statement

The authors have declared no competing interest.

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

사람과-쥐에서-dnah3의-양성-병원성-변이가-남성-불임을-유발한다


사람과 쥐에서 DNAH3의 양성 병원성 변이가 남성 불임을 유발한다



CDH1 유전자 변이는 유전성 소엽성 유방암 증후군과 연관되어 있으며, BRCA1/2 유전자 변이와는 구별되는 새로운 유형의 유전성 유방암 증후군을 나타낸다.


Data suggest the value of performing the CDH1 test on women under age 45 years, said a researcher.

CDH1 Linked With New Hereditary Breast Cancer Syndrome

유전성-유방암-증후군과-연관된-새로운-cdh1-유전자-발견


유전성 유방암 증후군과 연관된 새로운 CDH1 유전자 발견



유전성 아밀로이드증은 TTR 유전자의 병원성 변이로 인해 발생하는 자가우성 질환으로, 다양한 증상과 예후를 보이지만 최근 치료법 개발로 새로운 희망이 생겨났다.


The heterogeneity of hereditary amyloidosis can delay diagnosis and seriously affect prognosis and patient quality of life; these five things are need-to-know.

Hereditary Amyloidosis: 5 Things to Know

유전성-아밀로이드증-알아야-할-5가지


유전성 아밀로이드증: 알아야 할 5가지



Khdc3 유전자 돌연변이가 있는 조상을 가진 야생형 마우스에서 간 대사 유전자의 지속적인 발현 이상이 관찰되며, 이는 DNA 변이 없이도 세대를 거쳐 전달된다.


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

유전자-변이가-없어도-후대에-대사-이상이-지속되는-현상-khdc3-유전자-돌연변이의-초세대-영향


유전자 변이가 없어도 후대에 대사 이상이 지속되는 현상: Khdc3 유전자 돌연변이의 초세대 영향



마우스에서 전달되지 않은 부계 대립 유전자의 전세대 유전적 효과는 매우 드물며, 자연 발생 유전 변이 하에서 표현형 변이에 크게 기여하지 않을 것으로 보인다.


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

마우스-전사체에서-전달되지-않은-부계-대립-유전자의-전세대-효과에-대한-증거-부족


마우스 전사체에서 전달되지 않은 부계 대립 유전자의 전세대 효과에 대한 증거 부족
