"Nem tão doentes, nem tão livres de doença": narrativas de mulheres com câncer de mama sobre a investigação da herança genética em um instituto oncológico de pesquisa / "Ni tan enfermas, ni tan libres de la enfermidad": relatos de mujeres con cáncer de mama sobre la investigación de la herencia genética en un instituto de investigación oncológica / "Not so sick, not so disease-free": narratives of women with breast cancer about the investigation of genetic inheritance in an oncological research institute

A tese versa sobre a susceptibilidade hereditária para o câncer de mama sob um olhar socioantropológico. O tema apresenta relevância em função da atual valorização da genética na área da oncologia e dos impactos que esse campo da medicina produz na vida das pessoas e famílias envolvidas. A partir de uma produção etnográfica, buscou-se compreender como a prática do aconselhamento genético interfere em diversos planos da vida de mulheres com câncer de mama hereditário, como o psicoafetivo, social e familiar, atendidas por um instituto oncológico de pesquisa, pertencente ao setor privado de saúde. Para investigação metodológica, utilizou-se um conjunto de dados empíricos: entrevistas semiestruturadas com mulheres com (suspeita de) câncer de mama hereditário, observação de consultas com o serviço de genética e documentos online relativos à hereditariedade da doença na mama. Como resultados, constatou-se de que modos às percepções biomédicas acerca da noção de risco atravessaram a produção de subjetividades, identidades e coletividades das interlocutoras. Outros pontos explorados nas narrativas foram: as repercussões, individuais e coletivas, ocasionadas pela experiência do aconselhamento genético e o entrelaçamento da doença e da hereditariedade a outras vivências de cunho individual. O estudo visou contribuir a dar visibilidade às experiências e as demandas das mulheres investigadas e somar aos estudos risco, biotecnologias e subjetividades.AU

This thesis is about hereditary susceptibility to breast cancer from a socio-anthropological perspective. The theme is relevant due to the current appreciation of the genetics field in the oncological area and the impact on the lives of people and families involved. From an ethnographical starting point, how genetic counselling interferes with the life planning of women with hereditary breast cancer breast in areas such as psycho-affective, social and familiar. The search was conducted in an oncological research institute that belongs to the private healthcare system. For the methodological research, it was used a set of empirical data: semi-structured interviews with (suspected) hereditary breast cancer; participant observation of genetic consultations and online documents related to the heredity of the disease in the breast. As result, it has been noticed how the biomedical perceptions about the notion of risk cross through to the interlocutors' subjective productions, identities and sense of collective. Another aspect of the narratives is the relationship of genetics with oncological illness. It also stands out the individual and collective repercussions caused by the experience of genetic counselling and the intertwining of the disease and heredity with other individual experiences. The study aimed to contribute to giving visibility to the experiences and demands of the women investigated and also to add studies of the risk, biotechnologies and subjectivities.AU

La tesis aborda la susceptibilidad hereditaria al cáncer de mama desde una perspectiva socio-antropológica. El tema es relevante debido a la actual valorización de la genética en el área de la oncología y a los impactos que ese campo de la medicina tiene en la vida de las personas y familias. Con base en una producción etnográfica, buscamos comprender cómo la práctica del asesoramiento genético interfiere en diferentes áreas de la vida de mujeres con cáncer de mama hereditario, como el psicoafectivo, social y familiar, asistidas por un instituto de investigación oncológica, perteneciente al sector privado del cuidado de la salud. La investigación se fundamenta en un conjunto de datos empíricos: entrevistas semiestructuradas con mujeres con (sospecha de) cáncer de mama hereditario, observación de consultas en el servicio de genética y documentos en línea relacionados con la herencia familiar de la enfermedad. Como resultado, se constató como las percepciones sobre la biomedicina sobre la noción de riesgo atraviesan la producción de subjetividades, identidades y colectividades de las interlocutoras. Otros puntos explorados en las narrativas fueron: las repercusiones individuales y colectivas provocadas por la experiencia de la consejería genética y el entrelazamiento de la enfermedad y la herencia con otras experiencias de carácter individual. El estudio pretendió dar visibilidad a las experiencias y demandas de las mujeres investigadas y contribuir a los estudios sobre riesgo, biotecnologías y subjetividades. AU

Monogenic Causes of Strokes.

Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as COL4A1 syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.

Estimation of genetic parameters and relationships between type traits and milk yield of Holstein cows in Turkey / [Estimativa de parâmetros genéticos e relações entre características de tipo e produção de leite das vacas Holstein na Turquia]

In this study, milk yield, reproductive yield, and type traits of 533 Holstein cows in the first lactation raised in 54 farms were examined. In the three-year study, phenotypic (rP) and genetic (rG) correlations between type traits and milk yield were estimated based on the variance elements and heritability of the type traits of Holstein cows in the first lactation. Linear identification and scoring systems have been applied to classify the cows according to type traits. Heritability and correlations were estimated with ASREML models. The type traits included stature, angularity, rump width, hocks, rear udder height, central ligament, teat length, body capacity, feet and legs, udder composite and final score for genetic correlations with 305-day milk yield were estimated as -0.49, -0.14, -0.93, 0.35, 0.40, 0.11, -0.65, 0.70, 0.31, 0.54, and 0.70, for phenotypic correlations were estimated as 0.28, 0.28, 0.30, 0.21, 0.35, 0.39, -0.06, 0.46, 0.48, 0.56, and 0.58 respectively. Among the phenotypic correlations between the type traits, especially the phenotypic correlations between the final score and various type traits were found to be high and significant. The fact that these traits are in high correlation with other traits and milk yield may enable these to be used as indirect selection criteria in the selection for milk yield.(AU)

Neste estudo, foram examinadas a produção de leite, a produção reprodutiva e as características de tipo de 533 vacas Holstein na primeira lactação criadas em 54 fazendas. No estudo trienal, as correlações fenotípicas (rP) e genéticas (rG) entre características de tipo e produção de leite foram estimadas com base nos elementos de variação e hereditariedade das características de tipo das vacas Holstein na primeira lactação. Sistemas de identificação linear e de pontuação foram aplicados para classificar as vacas de acordo com os traços de tipo. A hereditariedade e correlações foram estimadas com os modelos ASREML. Os traços de tipo incluíam estatura, angularidade, largura da alcatra, jarretes, altura do úbere traseiro, ligamento central, comprimento das tetas, capacidade corporal, pés e patas, composição do úbere e pontuação final para correlações genéticas com a produção de leite de 305 dias foram estimados como -0. 49, -0,14, -0,93, 0,35, 0,40, 0,11, -0,65, 0,70, 0,31, 0,54, e 0,70, para correlações fenotípicas foram estimadas como 0,28, 0,28, 0,30, 0,21, 0,35, 0,39, -0,06, 0,46, 0,48, 0,56, e 0,58 respectivamente. Dentre as correlações fenotípicas entre os traços de tipo, especialmente as correlações fenotípicas entre a pontuação final e vários traços de tipo foram encontradas como altas e significativas. O fato destes traços estarem em alta correlação com outros traços e a produção de leite pode permitir que sejam usados como critérios de seleção indiretos na seleção para a produção de leite.(AU)

Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for disease.

Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for testis disease, prostate disease, kidney disease, lean pathology, and multiple disease. For these pathologies, sufficient numbers of individual males with only a single specific disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without disease were compared to identify the disease specific epimutation biomarkers. All pathologies were found to have disease specific DMRs and DHRs which were found to predominantly be distinct for each disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known disease linked genes. This is one of the first observations of potential sperm disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for disease susceptibility.

High-fat diet-induced and genetically inherited obesity differentially alters DNA methylation profile in the germline of adult male rats.

BACKGROUND: Paternal obesity has been associated with reduced live birth rates. It could lead to inheritance of metabolic disturbances to the offspring through epigenetic mechanisms. However, obesity is a multifactorial disorder with genetic or environmental causes. Earlier we had demonstrated differential effects of high-fat diet-induced obesity (DIO) and genetically inherited obesity (GIO) on metabolic, hormonal profile, male fertility, and spermatogenesis using two rat models. The present study aimed to understand the effect of DIO and GIO on DNA methylation in male germline, and its subsequent effects on the resorbed (post-implantation embryo loss) and normal embryos. First, we assessed the DNA methylation enzymatic machinery in the testis by Real-Time PCR, followed global DNA methylation levels in spermatozoa and testicular cells by ELISA and flow cytometry, respectively. Further, we performed Methylation Sequencing in spermatozoa for both the groups. Sequencing data in spermatozoa from both the groups were validated using Pyrosequencing. Expression of the differentially methylated genes was assessed in the resorbed and normal embryos sired by the DIO group using Real-Time PCR for functional validation. RESULTS: We noted a significant decrease in Dnmt transcript and global DNA methylation levels in the DIO group and an increase in the GIO group. Sequencing analysis showed 16,966 and 9113 differentially methylated regions in the spermatozoa of the DIO and GIO groups, respectively. Upon pathway analysis, we observed genes enriched in pathways involved in embryo growth and development namely Wnt, Hedgehog, TGF-beta, and Notch in spermatozoa for both the groups, the methylation status of which partially correlated with the gene expression pattern in resorbed and normal embryos sired by the DIO group. CONCLUSION: Our study reports the mechanism by which diet-induced and genetically inherited obesity causes differential effects on the DNA methylation in the male germline that could be due to a difference in the white adipose tissue accumulation. These differences could either lead to embryo loss or transmit obesity-related traits to the offspring in adult life.

Caracterização fenotípica de vacas F1 Holandês x Zebu de diferentes bases maternas / [Phenotypic characterization of Holsteins x Zebu F1 cows from different maternal bases]

Caracterizaram-se fêmeas F1 Holandês x Zebu de diferentes bases maternas quanto às pelagens, despigmentações e características morfométricas. Foram utilizadas 266 fêmeas F1, progênies do cruzamento de 26 touros da raça Holandesa com fêmeas de composição genética zebuínas: Gir, Nelore, Guzonel, Nelogir. Foram aplicadas análise de distribuição de frequência para características qualitativas e medidas de dispersão e tendência central para características morfométricas, e as médias foram comparadas pelo teste de Tukey a 5% de probabilidade. Acima de 60,0% dos animais foram de pelagem preta. As vacas que tiveram origem na raça Gir apresentaram comprimento de cabeça 2,8cm maior (P<0,05) que as fêmeas da raça Nelore. O comprimento da orelha variou (P<0,05) conforme a base materna utilizada. As vacas com genes da raça Nelore são 5,0cm mais altas (P<0,05). O perímetro torácico foi a característica morfométrica que teve correlação fenotípica de elevada magnitude com o peso, acima de 0,70, para as fêmeas das bases maternas Gir, Nelore e Nelogir. A pelagem não é indicativa da base materna utilizada. As vacas F1 de base materna Gir tiveram estrutura corporal menor que as fêmeas que portam genes da raça Nelore.(AU)

F1 Holstein x Zebu females from different maternal bases were characterized regarding coat, depigmentation and morphometric characteristics. A total of 266 F1 female progenies from the crossbreeding of 26 Holstein bulls with females of Zebu genetic composition were used: Gir, Nellore, Guzonel, Nellogir. Frequency distribution analysis was applied for qualitative characteristics and dispersion measures and central tendency for morphometric characteristics, and means were compared by Tukey test at 5% probability. Over 60.0% of the animals had a black coat. The cows that originated from the Gir breed had a head length of 2.8cm (P<0.05) higher than the Nellore females. Ear length varied (P<0.05) according to the maternal base used. Cows with Nelore genes were 5.0cm taller (P<0.05). The thoracic perimeter was the morphometric characteristic that had a high magnitude phenotypic correlation with weight, above 0.70, for the females of the Gir, Nellore and Nellogir maternal bases. The coat is not indicative of the maternal base used. F1 Gir-based cows had a smaller body structure than females with Nellore genes.(AU)

Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance.

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the environment-sensitive de novo activity ('tuner') and maintenance activity ('stabilizer') of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance.

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Single-Cell Tracing Dissects Regulation of Maintenance and Inheritance of Transcriptional Reinduction Memory.

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations. By applying pedigree analysis, we dissected and quantified the maintenance and inheritance of transcriptional reinduction memory in individual cells through multiple divisions. We systematically screened for loss- and gain-of-memory knockouts to identify memory regulators in thousands of single cells. We identified new loss-of-memory mutants, which affect memory inheritance into progeny. We also unveiled a gain-of-memory mutant, elp6Δ, and suggest that this new phenotype can be mediated through decreased histone occupancy at the GAL1 promoter. Our work uncovers principles of maintenance and inheritance of gene expression states and their regulators at the single-cell level.

Inheritance and Molecular Characterization of a Novel Mutated AHAS Gene Responsible for the Resistance of AHAS-Inhibiting Herbicides in Rapeseed (Brassica napus L.).

The use of herbicides is an effective and economic way to control weeds, but their availability for rapeseed is limited due to the shortage of herbicide-resistant cultivars in China. The single-point mutation in the acetohydroxyacid synthase (AHAS) gene can lead to AHAS-inhibiting herbicide resistance. In this study, the inheritance and molecular characterization of the tribenuron-methyl (TBM)-resistant rapeseed (Brassica napus L.) mutant, K5, are performed. Results indicated that TBM-resistance of K5 was controlled by one dominant allele at a single nuclear gene locus. The novel substitution of cytosine with thymine at position 544 in BnAHAS1 was identified in K5, leading to the alteration of proline with serine at position 182 in BnAHAS1. The TBM-resistance of K5 was approximately 100 times that of its wild-type ZS9, and K5 also showed cross-resistance to bensufuron-methyl and monosulfuron-ester sodium. The BnAHAS1544T transgenic Arabidopsis exhibited higher TBM-resistance than that of its wild-type, which confirmed that BnAHAS1544T was responsible for the herbicide resistance of K5. Simultaneously, an allele-specific marker was developed to quickly distinguish the heterozygous and homozygous mutated alleles BnAHAS1544T. In addition, a method for the fast screening of TBM-resistant plants at the cotyledon stage was developed. Our research identified and molecularly characterized one novel mutative AHAS allele in B. napus and laid a foundation for developing herbicide-resistant rapeseed cultivars.

A new biological definition of life.

Here we have proposed a new biological definition of life based on the function and reproduction of existing genes and creation of new ones, which is applicable to both unicellular and multicellular organisms. First, we coined a new term "genetic information metabolism" comprising functioning, reproduction, and creation of genes and their distribution among living and non-living carriers of genetic information. Encompassing this concept, life is defined as organized matter that provides genetic information metabolism. Additionally, we have articulated the general biological function of life as Tetz biological law: "General biological function of life is to provide genetic information metabolism" and formulated novel definition of life: "Life is an organized matter that provides genetic information metabolism". New definition of life and Tetz biological law allow to distinguish in a new way living and non-living objects on Earth and other planets based on providing genetic information metabolism.

Protein-based inheritance.

Epigenetic mechanisms of inheritance have come to occupy a prominent place in our understanding of living systems, primarily eukaryotes. There has been considerable and lively discussion of the possible evolutionary significance of transgenerational epigenetic inheritance. One particular type of epigenetic inheritance that has not figured much in general discussions is that based on conformational changes in proteins, where proteins with altered conformations can act as templates to propagate their own structure. An increasing number of such proteins - prions and prion-like - are being discovered. Phenotypes due to the structurally altered proteins are transmitted along with their structures. This review discusses the properties and implications of "classical" amyloid-forming prions, as well as the broader class of proteins with intrinsically disordered domains, which are proving to have fascinating properties that appear to play important roles in cell organisation and function, especially during stress responses.

A task that remains before us: Reconsidering inheritance as a biosocial phenomenon.

What doesit mean to inherit? Debates about the meaning of inheritance are numerous in the history and the present of the biological and the social sciences. While the majority of contributions in this special issue discuss hitherto unthought of molecular mechanisms of biological inheritance, this review explores the contested territory of inheritance from a social science perspective. Specifically, it examines contemporary biological research on epigenetic forms of inheritance in its historical and social contexts. To that end, the review explores what biology itself has been inheriting when it comes to how it considers inheritance conceptually and experimentally. I delineate three particularly important strands of inheritance: inheriting a history of eugenics; inheriting determinist reasoning; and inheriting experimental reductionism. I approach the social and scientific meaning of these inheritances by following scholars such as Donna Haraway and Jacques Derrida, who frame inheritance not as a passive occurrence but as an active process, as a task that must be undertaken by those who inherit. Such a framing raises the question of what it might mean to inherit something responsibly - particularly when what needs to be inherited is not an object but a difficult history. I argue that in order to become 'response-able' to this question, researchers who investigate biological inheritance today must engage these histories critically and review their legacies in present-day research. This is a task biologists might not want to undertake alone, but in interdisciplinary collaboration with social scientists and humanities scholars, in order to mobilize multiple forms of expertise for understanding the complex biosocial processes of human inheritance.

Chromosomal inheritance of parental rDNAs distribution pattern detected by FISH in diploid F1 hybrid progeny of Cobitis (Teleostei, Cobitidae) species has non-Mendelian character.

This study was conducted to describe the major and the minor rDNA chromosome distribution in the spined loach Cobitis taenia (2n = 48) and the Danubian loach Cobitis elongatoides (2n = 50), and their laboratory-produced diploid reciprocal F1 hybrid progeny. It was tested by fluorescence in situ hybridisation (FISH) whether the number of 28s and 5s rDNA sites in the karyotypes of diploid hybrids corresponds to the expectations resulting from Mendelian ratio and if nucleolar organiser regions (NOR)were inherited from both parents or nucleolar dominance can be observed in the induced F1 hybrid progeny. Ten (females) or twelve (males) 28s rDNA loci were located in nine uniarm chromosomes of C. taenia. Two of such loci terminally bounded on one acrocentric chromosome were unique and indicated as specific for this species. Large 5s rDNA clusters were located on two acrocentric chromosomes. In C. elongatoides of both sexes, six NOR sites in terminal regions on six meta-submetacentric chromosomes and two 5s rDNA sites on large submetacentrics were detected. The F1 hybrid progeny (2n = 49) was characterised by the intermediate karyotype with the sites of ribosome synthesis on chromosomes inherited from both parents without showing nucleolar dominance. 5s rDNA sites were detected on large submetacentric and two acrocentric chromosomes. The observed number of both 28s and 5s rDNAs signals in F1 diploid Cobitis hybrids was disproportionally inherited from the two parental species, showing inconsistency with the Mendelian ratios. The presented rDNA patterns indicate some marker chromosomes that allow the species of the parental male and female to be recognised in hybrid progeny. The 5s rDNA was found to be a particularly effective diagnostic marker of C. elongatoides to partially discern genomic composition of diploid Cobitis hybrids and presumably allopolyploids resulting from their backcrossing with one of the parental species. Thus, the current study provides insight into the extent of rDNA heredity in Cobitis chromosomes and their cytotaxonomic character.

Genetic relationship of litter traits between farrowing and weaning in Landrace and Large White pigs.

We estimated genetic parameters in Landrace and Large White pig populations for litter traits at farrowing (total number born, number born alive, number stillborn, total litter weight at birth (LWB), and mean litter weight at birth) and those at weaning (litter size at weaning (LSW), total litter weight at weaning (LWW), mean litter weight at weaning (MWW), and survival rate from farrowing to weaning). We analyzed 65,579 records at farrowing and 6,306 at weaning for Landrace, and 52,557 and 5,360, respectively, for Large White. Single-trait and two-trait repeatability animal models were exploited to estimate heritability and genetic correlation respectively. Heritability estimates of LSW were 0.09 for Landrace and 0.08 for Large White. Genetic correlations of LSW with MWW were -0.43 for Landrace and -0.24 for Large White. Genetic correlations of LSW with LWW and LWB ranged from 0.5 to 0.6. The genetic correlation of MWW with LWW was positive, but that with LWB was negligible. The results indicate that utilizing LWW or LWB could improve LSW efficiently, despite the antagonistic genetic correlation between LSW and MWW.

Estimating the Genome-wide Mutation Rate with Three-Way Identity by Descent.

The two primary methods for estimating the genome-wide mutation rate have been counting de novo mutations in parent-offspring trios and comparing sequence data between closely related species. With parent-offspring trio analysis it is difficult to control for genotype error, and resolution is limited because each trio provides information from only two meioses. Inter-species comparison is difficult to calibrate due to uncertainty in the number of meioses separating species, and it can be biased by selection and by changing mutation rates over time. An alternative class of approaches for estimating mutation rates that avoids these limitations is based on identity by descent (IBD) segments that arise from common ancestry within the past few thousand years. Existing IBD-based methods are limited to highly inbred samples, or lack robustness to genotype error and error in the estimated demographic history. We present an IBD-based method that uses sharing of IBD segments among sets of three individuals to estimate the mutation rate. Our method is applicable to accurately phased genotype data, such as parent-offspring trio data phased using Mendelian rules of inheritance. Unlike standard parent-offspring analysis, our method utilizes distant relationships and is robust to genotype error. We apply our method to data from 1,307 European-ancestry individuals in the Framingham Heart Study sequenced by the NHLBI TOPMed project. We obtain an estimate of 1.29 × 10-8 mutations per base pair per meiosis with a 95% confidence interval of [1.02 × 10-8, 1.56 × 10-8].

Genetic parameters for litter traits at different parities in purebred Landrace and Yorkshire pigs.

Comparison of the multi-trait animal model and the traditional repeatability model was carried out using data obtained from 6,424 Landrace and 20,835 Yorkshire sows farrowed from January 2000 to April 2018 in order to estimate genetic parameters for litter traits at different parities. Specifically, records of the total number born (TNB), number born alive (NBA), total number of mortality (MORT), number of stillborn (NSB) and number of mummified pigs (MUM) were used. Although results showed the heterogeneity of heritability for litter traits at different parities, the mean heritability estimates from the multi-trait model were found to be higher than those of the repeatability model for all traits in both pig breeds. In terms of genetic correlation between parities, a slight difference in genetic control in the first parity was noted for TNB and NBA in Landrace and Yorkshire pigs. The correlation between the first parity and later parities ranged from 0.48 to 0.74 for TNB and NBA in both breeds. Moreover, genetic correlation between parities for MORT and NSB was observed to be high for parities higher than 2 in Yorkshire pigs. For MUM, genetic correlation between the first and other parities was generally low in both breeds, indicating that culling pigs on the basis of MUM at the first parity could probably be unreasonable. Overall, the results of this study suggest that the multi-trait approach for litter size traits is useful for the accurate estimation of genetic parameters.

Genetic and Environmental Influences on Different Forms of Bullying Perpetration, Bullying Victimization, and Their Co-occurrence.

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was ~ 70% for perpetration and ~ 65% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (~ 71%) and especially physical (~ 77%) and mostly by environmental factors for relational perpetration and victimization (~ 60%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health.

BACKGROUND: A defining feature of sexual reproduction is the transmission of genomic information from both parents to the offspring. There is now compelling evidence that the inheritance of such genetic information is accompanied by additional epigenetic marks, or stable heritable information that is not accounted for by variations in DNA sequence. The reversible nature of epigenetic marks coupled with multiple rounds of epigenetic reprogramming that erase the majority of existing patterns have made the investigation of this phenomenon challenging. However, continual advances in molecular methods are allowing closer examination of the dynamic alterations to histone composition and DNA methylation patterns that accompany development and, in particular, how these modifications can occur in an individual's germline and be transmitted to the following generation. While the underlying mechanisms that permit this form of transgenerational inheritance remain unclear, it is increasingly apparent that a combination of genetic and epigenetic modifications plays major roles in determining the phenotypes of individuals and their offspring. OBJECTIVE AND RATIONALE: Information pertaining to transgenerational inheritance was systematically reviewed focusing primarily on mammalian cells to the exclusion of inheritance in plants, due to inherent differences in the means by which information is transmitted between generations. The effects of environmental factors and biological processes on both epigenetic and genetic information were reviewed to determine their contribution to modulating inheritable phenotypes. SEARCH METHODS: Articles indexed in PubMed were searched using keywords related to transgenerational inheritance, epigenetic modifications, paternal and maternal inheritable traits and environmental and biological factors influencing transgenerational modifications. We sought to clarify the role of epigenetic reprogramming events during the life cycle of mammals and provide a comprehensive review of how the genomic and epigenomic make-up of progenitors may determine the phenotype of its descendants. OUTCOMES: We found strong evidence supporting the role of DNA methylation patterns, histone modifications and even non-protein-coding RNA in altering the epigenetic composition of individuals and producing stable epigenetic effects that were transmitted from parents to offspring, in both humans and rodent species. Multiple genomic domains and several histone modification sites were found to resist demethylation and endure genome-wide reprogramming events. Epigenetic modifications integrated into the genome of individuals were shown to modulate gene expression and activity at enhancer and promoter domains, while genetic mutations were shown to alter sequence availability for methylation and histone binding. Fundamentally, alterations to the nuclear composition of the germline in response to environmental factors, ageing, diet and toxicant exposure have the potential to become hereditably transmitted. WIDER IMPLICATIONS: The environment influences the health and well-being of progeny by working through the germline to introduce spontaneous genetic mutations as well as a variety of epigenetic changes, including alterations in DNA methylation status and the post-translational modification of histones. In evolutionary terms, these changes create the phenotypic diversity that fuels the fires of natural selection. However, rather than being adaptive, such variation may also generate a plethora of pathological disease states ranging from dominant genetic disorders to neurological conditions, including spontaneous schizophrenia and autism.