Trisomy 21 with Maternally Inherited Balanced Translocation (15q;22q) in a Female Fetus: A Rare Case of Probable Interchromosomal Effect.

Chromosomal rearrangements can interfere with the disjunction and segregation of other chromosome pairs not involved in the rearrangements, promoting the occurrence of numerical abnormalities in resulting gametes and predisposition to trisomy in offspring. This phenomenon of interference is known as the interchromosomal effect (ICE). Here we report a prenatal case potentially generated by ICE. The first-trimester screening ultrasound of the pregnant woman was normal, but the NIPT indicated a high risk for three copies of chromosome 21, thus suspecting trisomy 21 (T21). After a comprehensive clinical evaluation and genetic counseling, the couple decided to undergo amniocentesis. The prenatal karyotype confirmed T21 but also showed a balanced translocation between the long arm of chromosome 15 (q22) and the long arm of chromosome 22. The parents' karyotypes also showed that the mother had the 15;22 translocation. We reviewed T21 screening methods, and we performed a literature review on ICE, a generally overlooked phenomenon. We observed that ours is the first report of a prenatal case potentially due to ICE derived from the mother. The recurrence risk of aneuploidy in the offspring of translocated individuals is likely slightly increased, but it is not possible to estimate to what extent. In addition to supporting observations, there are still open questions such as, how frequent is ICE? How much is the aneuploidy risk altered by ICE?

Delineating maternal influence in regulation of variance in major economic traits of White Leghorns: Bayesian insights.

Proper variance partitioning and estimation of genetic parameters at appropriate time interval is crucial for understanding the dynamics of trait variance and genetic correlations and for deciding the future breeding strategy of the population. This study was conducted on the same premise to estimate genetic parameters of major economic traits in a White Leghorn strain IWH using Bayesian approach and to identify the role of maternal effects in the regulation of trait variance. Three different models incorporating the direct additive effect (Model 1), direct additive and maternal genetic effect (Model 2) and direct additive, maternal genetic and maternal permanent environmental effects (Model 3) were tried to estimate the genetic parameters for body weight traits (birth weight, body weight at 16, 20, 40 and 52 weeks), Age at sexual maturity (ASM), egg production traits (egg production up to 24, 28, 40, 52, 64 and 72 weeks) and egg weight traits (egg weight at 28, 40 and 52 weeks). Model 2 and Model 3 with maternal effects were found to be the best having the highest accuracy for almost all the traits. The direct additive genetic heritability was moderate for ASM, moderate to high for body weight traits and egg weight traits and low to moderate for egg production traits. Though the maternal heritability (h2mat) and permanent environmental effect (c2mpe) was low (<0.1) for most of the traits, they formed an important component of trait variance. Traits like egg weight at 28 weeks (0.14±0.06) and egg production at 72 weeks (0.13±0.07) reported comparatively higher values for c2mpe and h2mat respectively. Additive genetic correlation was high and positive between body weight traits, between egg weight traits, between consecutive egg production traits and between body weight and egg weight traits. However, a negative genetic correlation existed between egg production and egg weight traits, egg production and body weight traits, ASM and early egg production traits. Overall, a moderate positive genetic correlation was estimated between ASM and body weight traits and ASM and egg weight traits. Based on our findings, we can deduce that maternal effects constitute an important source of variation for all the major economic traits in White Leghorn and should be necessarily considered in genetic evaluation programs.

Maternal regulation of the vertebrate oocyte-to-embryo transition.

Maternally-loaded factors in the egg accumulate during oogenesis and are essential for the acquisition of oocyte and egg developmental competence to ensure the production of viable embryos. However, their molecular nature and functional importance remain poorly understood. Here, we present a collection of 9 recessive maternal-effect mutants identified in a zebrafish forward genetic screen that reveal unique molecular insights into the mechanisms controlling the vertebrate oocyte-to-embryo transition. Four genes, over easy, p33bjta, poached and black caviar, were found to control initial steps in yolk globule sizing and protein cleavage during oocyte maturation that act independently of nuclear maturation. The krang, kazukuram, p28tabj, and spotty genes play distinct roles in egg activation, including cortical granule biology, cytoplasmic segregation, the regulation of microtubule organizing center assembly and microtubule nucleation, and establishing the basic body plan. Furthermore, we cloned two of the mutant genes, identifying the over easy gene as a subunit of the Adaptor Protein complex 5, Ap5m1, which implicates it in regulating intracellular trafficking and yolk vesicle formation. The novel maternal protein Krang/Kiaa0513, highly conserved in metazoans, was discovered and linked to the function of cortical granules during egg activation. These mutant genes represent novel genetic entry points to decipher the molecular mechanisms functioning in the oocyte-to-embryo transition, fertility, and human disease. Additionally, our genetic adult screen not only contributes to the existing knowledge in the field but also sets the basis for future investigations. Thus, the identified maternal genes represent key players in the coordination and execution of events prior to fertilization.

Maternal effects, reciprocal differences and combining ability study for yield and its component traits in maize (Zea mays L.) through modified diallel analysis.

Combining ability status of the inbred lines is crucial information for hybrid breeding program. Diallel or line × tester mating designs are frequently used to evaluate the combining ability. In the current study a modified diallel model was used, wherein the Griffing's combining ability effects were further partitioned to understand the effects due to maternal and reciprocal. To do this, eight parental lines of maize were crossed in full diallel method and the generated hybrids along with parents were phenotyped. The field data on the quantitative traits was analyzed using both Griffing's and the modified model to determine how well the parents' and the F1 hybrids combined. For each of the traits, a sizable reciprocal and maternal variance was observed. The number of kernel rows per cob variable had a ratio of additive variance to dominance variance greater than one. All other traits including grain yield had a ratio close to zero, suggesting that non-additive gene action was primarily responsible for the genetic control of most of the traits. The narrow sense heritability was low to moderate for majority of the variables, except for number of kernel rows per cob. With the help of the improved model, it was possible to choose superior parents and cross-parent pairings with accuracy. Based on the modified general combining ability effects and maternal effects, the parental line P5 was recognized as a potential female parent and P7 as a good male parent for grain yield and yield-attributing characteristics. The cross combination of P8×P1 had the highest specific combining ability effect on grain yield. P5×P6 cross had the highest reciprocal effect. The correlation analysis implies that the Griffing's general combining ability effects and specific combining ability effects were found to be less efficient in predicting F1 performance as compared to the modified model.

Maternal inheritance of functional centrioles in two parthenogenetic nematodes.

Centrioles are the core constituent of centrosomes, microtubule-organizing centers involved in directing mitotic spindle assembly and chromosome segregation in animal cells. In sexually reproducing species, centrioles degenerate during oogenesis and female meiosis is usually acentrosomal. Centrioles are retained during male meiosis and, in most species, are reintroduced with the sperm during fertilization, restoring centriole numbers in embryos. In contrast, the presence, origin, and function of centrioles in parthenogenetic species is unknown. We found that centrioles are maternally inherited in two species of asexual parthenogenetic nematodes and identified two different strategies for maternal inheritance evolved in the two species. In Rhabditophanes diutinus, centrioles organize the poles of the meiotic spindle and are inherited by both the polar body and embryo. In Disploscapter pachys, the two pairs of centrioles remain close together and are inherited by the embryo only. Our results suggest that maternally-inherited centrioles organize the embryonic spindle poles and act as a symmetry-breaking cue to induce embryo polarization. Thus, in these parthenogenetic nematodes, centrioles are maternally-inherited and functionally replace their sperm-inherited counterparts in sexually reproducing species.

Exploring the maternal inheritance transmitted by the oocyte to its progeny.

Fertility is declining worldwide and many couples are turning towards assisted reproductive technologies (ART) to conceive babies. Organisms that propagate via sexual reproduction often come from the fusion between two gametes, an oocyte and a sperm, whose qualities seem to be decreasing in the human species. Interestingly, while the sperm mostly transmits its haploid genome, the oocyte transmits not only its haploid set of chromosomes but also its huge cytoplasm to its progeny. This is what can be defined as the maternal inheritance composed of chromosomes, organelles, lipids, metabolites, proteins and RNAs. To decipher the decline in oocyte quality, it is essential to explore the nature of the maternal inheritance, and therefore study the last stages of murine oogenesis, namely the end of oocyte growth followed by the two meiotic divisions. These divisions are extremely asymmetric in terms of the size of the daughter cells, allowing to preserve the maternal inheritance accumulated during oocyte growth within these huge cells to support early embryo development. Studies performed in Marie-Hélène Verlhac's lab have allowed to discover the unprecedented impact of original acto-myosin based mechanisms in the constitution as well as the preservation of this maternal inheritance and the consequences when these processes go awry.

La fécondité diminue mondialement et de nombreux couples se tournent vers les techniques de procréation médicalement assistée (PMA) pour concevoir des bébés. Les organismes se propageant par reproduction sexuée sont souvent issus de la fusion de deux gamètes, un ovocyte et un spermatozoïde, dont les qualités semblent diminuer dans l'espèce humaine. Si le spermatozoïde transmet principalement son génome haploïde, l'ovocyte transmet à sa progéniture non seulement son lot haploïde de chromosomes, mais aussi son immense cytoplasme. C'est ce que l'on peut définir comme l'héritage maternel, composé de chromosomes, d'organelles, de lipides, de métabolites, de protéines et d'ARNs. Pour comprendre la baisse de qualité des ovocytes, il est essentiel d'explorer la nature de cet héritage maternel, et donc d'étudier les dernières étapes de l'ovogenèse murine, à savoir la fin de la croissance ovocytaire suivie des deux divisions méiotiques. Ces divisions sont extrêmement asymétriques par la taille des cellules filles engendrées, ce qui permet de préserver l'héritage maternel accumulé pendant la croissance de cette énorme cellule, l'ovocyte, pour soutenir le développement précoce de l'embryon. Les études menées dans le laboratoire de Marie-Hélène Verlhac ont permis de découvrir l'impact sans précédent de mécanismes originaux dépendant de l'acto-myosine dans la constitution et la préservation de cet héritage maternel, ainsi que les conséquences des erreurs dans ces processus.

Association of maternal genetics with the gut microbiome and eucalypt diet selection in captive koalas.

Background: Koalas, an Australian arboreal marsupial, depend on eucalypt tree leaves for their diet. They selectively consume only a few of the hundreds of available eucalypt species. Since the koala gut microbiome is essential for the digestion and detoxification of eucalypts, their individual differences in the gut microbiome may lead to variations in their eucalypt selection and eucalypt metabolic capacity. However, research focusing on the relationship between the gut microbiome and differences in food preferences is very limited. We aimed to determine whether individual and regional differences exist in the gut microbiome of koalas as well as the mechanism by which these differences influence eucalypt selection. Methods: Foraging data were collected from six koalas and a total of 62 feces were collected from 15 koalas of two zoos in Japan. The mitochondrial phylogenetic analysis was conducted to estimate the mitochondrial maternal origin of each koala. In addition, the 16S-based gut microbiome of 15 koalas was analyzed to determine the composition and diversity of each koala's gut microbiome. We used these data to investigate the relationship among mitochondrial maternal origin, gut microbiome and eucalypt diet selection. Results and Discussion: This research revealed that diversity and composition of the gut microbiome and that eucalypt diet selection of koalas differs among regions. We also revealed that the gut microbiome alpha diversity was correlated with foraging diversity in koalas. These individual and regional differences would result from vertical (maternal) transmission of the gut microbiome and represent an intraspecific variation in koala foraging strategies. Further, we demonstrated that certain gut bacteria were strongly correlated with both mitochondrial maternal origin and eucalypt foraging patterns. Bacteria found to be associated with mitochondrial maternal origin included bacteria involved in fiber digestion and degradation of secondary metabolites, such as the families Rikenellaceae and Synergistaceae. These bacteria may cause differences in metabolic capacity between individual and regional koalas and influence their eucalypt selection. Conclusion: We showed that the characteristics (composition and diversity) of the gut microbiome and eucalypt diet selection of koalas differ by individuals and regional origins as we expected. In addition, some gut bacteria that could influence eucalypt foraging of koalas showed the relationships with both mitochondrial maternal origin and eucalypt foraging pattern. These differences in the gut microbiome between regional origins may make a difference in eucalypt selection. Given the importance of the gut microbiome to koalas foraging on eucalypts and their strong symbiotic relationship, future studies should focus on the symbiotic relationship and coevolution between koalas and the gut microbiome to understand individual and regional differences in eucalypt diet selection by koalas.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

The quantitative genetic basis of variation in sexual versus non-sexual butterfly wing colouration: autosomal, Z-linked, and maternal effects.

Viability indicator traits are expected to be integrated extensively across the genome yet sex-limited to ensure that any benefits are sexually concordant. Understanding how such expectations are accommodated requires elucidating the quantitative genetic architecture of candidate traits in and across the sexes. Here we applied an animal modelling approach to partition the autosomal, allosomal, and direct maternal bases of variation in sexual versus non-sexual dorsal wing colouration in the butterfly Eurema hecabe. The sexual colour trait-coherently scattered ultraviolet that is under strong directional selection due to female choice-is brighter and more expansive in males, and overlays non-sexual pigmentary yellow markings that otherwise dominate both wing surfaces in each sex. Our modelling estimated high and sexually equivalent autosomal variances for ultraviolet reflectance (furnishing h2 ~ 0.58 overall and ~0.75 in males), accompanied by smaller but generally significant Z-linked and maternal components. By contrast, variation in non-sexual yellow was largely attributed to Z-linked sources. Intersexual genetic correlations based upon the major source of variation in each trait were high and not different from 1.0, implying regulation by a pool of genes common to each sex. An expansive autosomal basis for ultraviolet is consistent with its hypothesized role as a genome-wide viability indicator and ensures that both sons and daughters will inherit their father's attractiveness.

Estimation of additive and maternal covariance of production traits in Murrah buffalo.

The study was done to determine additive, maternal and common permanent environmental effects and best-suited model for some production traits using six univariate animal models that differed in the (co)variance components fitted to assess the importance of maternal effect using likelihood ratio test in Murrah buffaloes. Data from 614 Murrah buffaloes related to production traits were collected from history pedigree sheets maintained at the buffalo farm, Department of Livestock Production and Management (LPM), LUVAS, Hisar. The production traits under this study were 305 days milk yield (305DMY), peak yield (PY), lactation length (LL), dry period (DP), lactation milk yield (LMY) and wet average (WA). The heritability estimates were in the range of 0.33-0.44 for 305DMY, 0.25-0.51 for PY, 0.05-0.13 for LL, 0.03-0.23 for DP, 0.17-0.40 for LMY and 0.37-0.66 for WA. Model 1 was considered best for most of the traits, viz., 305DMY, PY, LL, LMY and WA followed by model 2 for DP. Covariance and correlated values within the traits caused inflation of heritability in model 3 and model 6. The maximum covariance between the additive and maternal effect was found in trait LMY, which was 14,183.90 in model 3 and the minimum value was also reported in the same trait for model 6, valued at -3522.37. Multivariate analysis showed that all production traits were moderate to high and positively correlated with each other except for DP, which was low and negative genetic and phenotypic correlated. Spearman's rank correlation coefficients of breeding value among all six models were high and significant, ranged from 0.78 to 1.00 for all the traits except DP, therefore any of the models could be taken into account depending upon the availability of data.

Phylogenetic Conflict Between Species Tree and Maternally Inherited Gene Trees in a Clade of Emberiza Buntings (Aves: Emberizidae).

Different genomic regions may reflect conflicting phylogenetic topologies primarily due to incomplete lineage sorting and/or gene flow. Genomic data are necessary to reconstruct the true species tree and explore potential causes of phylogenetic conflict. Here, we investigate the phylogenetic relationships of 4 Emberiza species (Aves: Emberizidae) and discuss the potential causes of the observed mitochondrial non-monophyly of Emberiza godlewskii (Godlewski's bunting) using phylogenomic analyses based on whole genome resequencing data from 41 birds. Analyses based on both the whole mitochondrial genome and ~39 kilobases from the non-recombining W chromosome reveal sister relationships between each the northern and southern populations of E. godlewskii with E. cioides and E. cia, respectively. In contrast, the monophyly of E. godlewskii is reflected by the phylogenetic signal of autosomal and Z chromosomal sequence data as well as demographic inference analyses, which-in combination-support the following tree topology: ([{E. godlewskii, E. cia}, E. cioides], E. jankowskii). Using D-statistics, we detected multiple gene flow events among different lineages, indicating pervasive introgressive hybridization within this clade. Introgression from an unsampled lineage that is sister to E. cioides or introgression from an unsampled mitochondrial + W chromosomal lineage of E. cioides into northern E. godlewskii may explain the phylogenetic conflict between the species tree estimated from genome-wide data versus mtDNA/W tree topologies. These results underscore the importance of using genomic data for phylogenetic reconstruction and species delimitation.

Molecular basis for maternal inheritance of human mitochondrial DNA.

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.

Mitochondrial genome study in blood of maternally inherited ALS cases.

BACKGROUND: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy. RESULTS: We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients. CONCLUSION: Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer's and Parkinson's diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.

Maternal plastid inheritance: two abating factors identified.

Organelle DNAs (orgDNAs) in mitochondria and plastids are generally inherited from the maternal parent; however, it is unclear how their inheritance mode is controlled, particularly in the plastids of seed plants. Chung et al. identify two factors that affect maternal inheritance in tobacco plastids: cold temperature and DNA amount in pollen.

The usefulness of maternally inherited genetic markers for phylogeographic studies in village chicken.

Phylogeography plays a major role in understanding micro and macroevolutionary processes dealing with evolutionary interpretations of geographical distribution. This field integrates information from molecular genetics, population genetics, demography, and phylogeny for the interpretation of the geographical distribution of lineages. The full mtDNA sequence and W chromosome polymorphisms were exploited to assess the usefulness of two maternally-inherited genetic markers for phylogeographic studies of village chickens. We studied 243 full mtDNA sequences from three countries (Iraq, n = 27; Ethiopia, n = 211; and Saudi Arabia, n = 5) and a 13-kb fragment of the W chromosome from 20 Iraqi and 137 Ethiopian female chickens. The results show a high level of genetic diversity for the mtDNA within and among countries as well as within populations. On the other hand, sequence analysis of the W chromosome shows low genetic diversity both within and among populations. Six full mtDNA haplogroups (A, B, C1, C2, D1, and E1) were observed and 25 distinct W haplotypes. The results support the effectiveness of full mtDNA sequences but not the W chromosome in tracing the maternal historical genome background with, however, weak within a country phylogeographic signal.

Investigating the Impact of a Curse: Diseases, Population Isolation, Evolution and the Mother's Curse.

The mitochondrion was characterized for years as the energy factory of the cell, but now its role in many more cellular processes is recognized. The mitochondrion and mitochondrial DNA (mtDNA) also possess a set of distinct properties, including maternal inheritance, that creates the Mother's Curse phenomenon. As mtDNA is inherited from females to all offspring, mutations that are harmful to males tend to accumulate more easily. The Mother's Curse is associated with various diseases, and has a significant effect on males, in many cases even affecting their reproductive ability. Sometimes, it even leads to reproductive isolation, as in crosses between different populations, the mitochondrial genome cannot cooperate effectively with the nuclear one resulting in a mito-nuclear incompatibility and reduce the fitness of the hybrids. This phenomenon is observed both in the laboratory and in natural populations, and have the potential to influence their evolution and speciation. Therefore, it turns out that the study of mitochondria is an exciting field that finds many applications, including pest control, and it can shed light on the molecular mechanism of several diseases, improving successful diagnosis and therapeutics. Finally, mito-nuclear co-adaptation, paternal leakage, and kin selection are some mechanisms that can mitigate the impact of the Mother's Curse.

Using adopted individuals to partition indirect maternal genetic effects into prenatal and postnatal effects on offspring phenotypes.

Maternal genetic effects can be defined as the effect of a mother's genotype on the phenotype of her offspring, independent of the offspring's genotype. Maternal genetic effects can act via the intrauterine environment during pregnancy and/or via the postnatal environment. In this manuscript, we present a simple extension to the basic adoption design that uses structural equation modelling (SEM) to partition maternal genetic effects into prenatal and postnatal effects. We examine the power, utility and type I error rate of our model using simulations and asymptotic power calculations. We apply our model to polygenic scores of educational attainment and birth weight associated variants, in up to 5,178 adopted singletons, 943 trios, 2687 mother-offspring pairs, 712 father-offspring pairs and 347,980 singletons from the UK Biobank. Our results show the expected pattern of maternal genetic effects on offspring birth weight, but unexpectedly large prenatal maternal genetic effects on offspring educational attainment. Sensitivity and simulation analyses suggest this result may be at least partially due to adopted individuals in the UK Biobank being raised by their biological relatives. We show that accurate modelling of these sorts of cryptic relationships is sufficient to bring type I error rate under control and produce asymptotically unbiased estimates of prenatal and postnatal maternal genetic effects. We conclude that there would be considerable value in following up adopted individuals in the UK Biobank to determine whether they were raised by their biological relatives, and if so, to precisely ascertain the nature of these relationships. These adopted individuals could then be incorporated into informative statistical genetics models like the one described in our manuscript to further elucidate the genetic architecture of complex traits and diseases.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Epigenetic, genetic and maternal effects enable stable centromere inheritance.

Centromeres are defined epigenetically by the histone H3 variant CENP-A. The propagation cycle by which pre-existing CENP-A nucleosomes serve as templates for nascent assembly predicts the epigenetic memory of weakened centromeres. Using a mouse model with reduced levels of CENP-A nucleosomes, we find that an embryonic plastic phase precedes epigenetic memory through development. During this phase, nascent CENP-A nucleosome assembly depends on the maternal Cenpa genotype rather than the pre-existing template. Weakened centromeres are thus limited to a single generation, and parental epigenetic differences are eliminated by equal assembly on maternal and paternal centromeres. These differences persist, however, when the underlying DNA of parental centromeres differs in repeat abundance, as assembly during the plastic phase also depends on sufficient repetitive centromere DNA. With contributions of centromere DNA and the Cenpa maternal effect, we propose that centromere inheritance naturally minimizes fitness costs associated with weakened centromeres or epigenetic differences between parents.

Bayesian analysis reveals the influence of maternal effect on pre-weaning body weights in Landlly piglets.

The present study was undertaken to estimate the (co)variance components and genetic parameters of body weights recorded in Landlly piglets from birth to weaning at weekly intervals (w0 to w6). The data pertained to body weights of 2462 piglets, born to 91 sires and 159 dams across different generations during a 7-year period from 2014 to 2020. Five animal models (I-V), differentiated by inclusion or exclusion of maternal effects with or without covariance between maternal and direct genetic effects, were fitted on the data using the Bayesian algorithm. The analyses were implemented by Gibbs sampling in the BLUPF90 program and Markov chain Monte Carlo (MCMC) methodology was used to draw samples of posterior distribution pertaining to (co)variance components. Based on deviance information criteria (DIC), model V with inclusion of direct additive genetic, direct maternal genetic and permanent environmental effect of dam as random factors along with covariance between direct additive and maternal effects best fitted the data on pre-weaning traits (w0 to w5). Whereas, model I incorporating only the direct additive genetic effect best fitted the weaning weight (w6) data in Landlly piglets. The posterior mean estimates of direct heritability under the best models for W0 to W6 were 0.13, 0.19, 0.29, 0.13, 0.26, 0.32 and 0.46, respectively. Inclusion of the maternal component helped in better partitioning of variance for different body weights in Landlly piglets. The maternal heritability ranged from 0.06 to 0.14, while the litter heritability ranged from 0.11 to 0.15 for pre-weaning weights (W0 to W5) under the best-fit models. The influence of maternal environment was greater than maternal genetic effect from birth to 4th week of age. The results implied that variations in body weight of Landlly pigs were genetically controlled to moderate levels (especially w2 and w4) with contributions from direct additive and maternal genotype that can be exploited by designing efficient breeding programmes.