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Forkhead box (FOX) proteins are members of a conserved family of transcription factors. Pathogenic variants in FOX genes have been shown to be responsible for several human genetic diseases. Here, we have studied the molecular and structural features of germline pathogenic variants in seven FOX proteins involved in Mendelian disorders and compared them with those of variants present in the general population (gnomAD). Our study shows that the DNA-binding domain of FOX proteins is particularly sensitive to damaging variation, although some family members show greater mutational tolerance than others. Next, we set to demonstrate that this tolerance depends on the inheritance mode of FOX-linked disorders. Accordingly, genes whose variants underlie recessive conditions are supposed to have a greater tolerance to variation. This is what we found. As expected, variants responsible for disorders with a dominant inheritance pattern show a higher degree of pathogenicity compared to those segregating in the general population. Moreover, we show that pathogenic and likely pathogenic variants tend to affect mutually exclusive sites with respect to those reported in gnomAD. The former also tend to affect sites with lower solvent exposure and a higher degree of conservation. Our results show the value of using publicly available databases and bioinformatics to gain insights into the molecular and structural bases of disease-causing genetic variation.

Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients' induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.

Backgrounds MUTYH‐associated polyposis (MAP) is an autosomal recessive disease caused by biallelic pathogenic variants (PV) of the MUTYH gene. The aim of this study was to investigate the genetic causes of unexplained polyposis patients with monoallelic MUTYH PV. The analysis focused on 26 patients with suspected MAP, belonging to 23 families. Ten probands carried also one or more additional MUTYH variants of unknown significance. Methods Based on variant type and on the collected clinical and molecular data, these variants were reinterpreted by applying the ACMG/AMP rules. Moreover, supplementary analyses were carried out to investigate the presence of other variants and copy number variations in the coding and promoter regions of MUTYH, as well as other polyposis genes (APC, NTHL1, POLE, POLD1, MSH3, RNF43, and MCM9). Results We reclassified 4 out of 10 MUTYH variants as pathogenic or likely pathogenic, thus supporting the diagnosis of MAP in only four cases. Two other patients belonging to the same family showed a previously undetected deletion of the APC gene promoter. No PVs were found in the other investigated genes. However, 6 out of the 18 remaining families are still interesting MAP candidates, due to the co‐presence of a class 3 MUTYH variant that could be reinterpreted in the next future. Conclusion Several efforts are necessary to fully elucidate the genetic etiology of suspected MAP patients, especially those with the most severe polyposis/tumor phenotype. Clinical data, tumor molecular profile, family history, and polyposis inheritance mode may guide variant interpretation and address supplementary studies., The aim of this study was to investigate the genetic causes of unexplained polyposis patients with monoallelic MUTYH pathogenic variants. Clinical data, tumor molecular profile, family history, and polyposis inheritance mode may guide MUTYH variant interpretation and address supplementary studies of additional polyposis risk genes.

Background Pathogenic variants in human phospholamban coding gene (PLN) are known to cause hereditary dilated cardiomyopathy with heart failure in an autosomal dominant mode. Methods We performed high-depth targeted next-generation sequencing using a cardiomyopathy-panel containing 80 disease-related genes in 650 unrelated patients with non-ischemic cardiomyopathy to identify potential pathogenic PLN variants. To comprehensively evaluate the genetic cause of the proband and his pedigree, whole-exome sequencing and Sanger sequencing were performed. Results A novel homozygous nonsense variant (p.Glu2Ter, c.4G>T) in PLN was identified in a 36-year-old male suffering from dilated cardiomyopathy with severe heart failure. No more cardiomyopathy-causing variant or likely pathogenic copy number variation was identified. This variant was not detected in 800 unrelated healthy controls. Furthermore, the variant is not in the Exome Aggregation Consortium or the Genome Aggregation databases. Western blots showed that this variant significantly reduced the expression of phospholamban. Furthermore, in pedigree analysis, we found that all five heterozygous PLN-p.Glu2Ter carriers (including four elder relatives) had normal heart size and cardiac function, which revealed a novel autosomal recessive inheritance mode. Conclusions Our study identified a novel pathogenic variant of PLN, and revealed a novel pathogenic inheritance mode of PLN causing dilated cardiomyopathy with heart failure.

Along with traditional effects of aging and carcinogen exposure—inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.

Mutation rate plays an important role in adaptive evolution due to its effect on the rate of appearance of both beneficial and deleterious mutations and is therefore subject to second-order selection. The mutation rate varies between and within species and populations, increases under some stresses, and can be modified by mutator and anti-mutator alleles. It may also vary among genetically identical individuals: empirical evidence from bacteria suggests that the mutation rate can be affected by translation errors and expression noise in various proteins. Importantly, this non-genetic variation may be heritable via a transgenerational epigenetic mode of inheritance, giving rise to mutator phenotype switching that is independent from mutator alleles. Here we investigate mathematically how the rate of adaptive evolution on rugged, complex fitness landscapes is affected by the rate of mutation rate phenotype switching. Motivated by recent experimental results of mutation rate variation, we model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. Thus, the mutation rate can be interpreted as a genetically inherited trait when the switching rate is low, as an epigenetically inherited trait when the switching rate is intermediate, or as a randomly determined trait when the switching rate is high. We find that intermediate switching rates maximize the rate of adaptation on rugged fitness landscapes. This is because an intermediate switching rate can maintain within the same individuals both a mutator phenotype and pre-existing mutations, a combination that facilitates the crossing of fitness valleys. Further, intermediate switching rates allow the population to quickly revert to a low mutation rate after adaptation is achieved, avoiding the accumulation of deleterious mutations linked to mutator alleles. Our results rationalize recently observed noise in the expression of proteins that affect the mutation rate and suggest that non-genetic inheritance of this phenotype may facilitate evolutionary adaptive processes.

Metazoans usually reproduce sexually, blending the unique identity of parental genomes for the next generation through functional crossing-over and recombination in meiosis. However, some metazoan lineages have evolved reproductive systems where offspring are either full (clonal) or partial (hemiclonal) genetic replicas. In the latter group, the process of uniparental genome elimination selectively eliminates either the maternal or paternal genome from germ cells, and only one parental genome is selected for transmission. Although fairly common in plants, hybridogenesis (i.e., clonal haploidization via chromosome elimination) remains a poorly understood process in animals. Here, we explore the proximal cytogenomic mechanisms of somatic and germ cell chromosomes in sexual and hybrid genotypes of Australian carp gudgeons (Hypseleotris) by tracing the fate of each set during mitosis (in somatic tissues) and meiosis (in gonads). Our comparative study of diploid hybrid and sexual individuals revealed visually functional gonads in male and female hybrid genotypes and generally high karyotype variability, although the number of chromosome arms remains constant. Our results delivered direct evidence for classic hybridogenesis as a reproductive mode in carp gudgeons. Two parental sets with integral structure in the hybrid soma (the F1 constitution) contrasted with uniparental chromosomal inheritance detected in gonads. The inheritance mode happens through premeiotic genome duplication of the parental genome to be transmitted, whereas the second parental genome is likely gradually eliminated already in juvenile individuals. The role of metacentric chromosomes in hybrid evolution is also discussed.

Forensic genetic laboratories perform a large amount of STR analyses of the Y chromosome, in particular to analyze the male part of complex DNA mixtures. However, the statistical interpretation of evidence retrieved from Y-STR haplotypes is challenging. Due to the uni-parental inheritance mode, Y-STR loci are connected to each other and thus haplotypes show patterns of relationship on the familial and population level. This precludes the treatment of Y-STR loci as independently inherited variables and the application of the product rule. Instead, the dependency structure of Y-STRs needs to be included in the haplotype frequency estimation process affecting also the current paradigm of a random match probability that is in the autosomal case approximated by the population frequency assuming unrelatedness of sampled individuals. Information on the degree of paternal relatedness in the suspect population as well as on the familial network is however needed to interpret Y-chromosomal results in the best possible way. The previous recommendations of the DNA commission of the ISFG on the use of Y-STRs in forensic analysis published more than a decade ago [1] cover the interpretation issue only marginally. The current recommendations address a number of topics (frequency estimators, databases, metapopulations, LR formulation, triage, rapidly mutating Y-STRs) with relevance for the Y-STR statistics and recommend a decision-based procedure, which takes into account legal requirements as well as availability of population data and statistical methods.

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

FBLN5-related cutis laxa (CL) is a rare syndrome that can be inherited in an autosomal dominant or recessive manner. Autosomal recessive cutis laxa (ARCL), type IA, has been reported to be more severe. The disease is characterized by microcephaly, sagging cheeks, loose, wrinkled and redundant skin, emphysema, aorta or pulmonary artery abnormalities, inguinal hernia, and anomalies of internal organs. Homozygous mutations in the FBLN5 gene are responsible for the clinical manifestations. We report a family study of a child with ARCL. FBLN5 genes of the patient and parents were sequenced using next-generation sequencing technologies. Analyses showed that the patient was homozygous for the novel c.518A>G, p.R173H mutation in exon 6 of the FBLN5 gene, whereas the parents were heterozygous. The mutation was found to be 'possibly pathogenic' in bioinformatic analysis. We identified a novel FBLN5 mutation in a CL patient; pedigree and parental genetic analyses suggested ARCL. Our results also suggest that the mutation analysis provides useful evidence to support the clinical diagnosis and define the inheritance mode of CL in an apparently sporadic case.

International audience; Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (460 causative genes), 40–70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS.

Hereditary spastic paraplegia (HSP) includes a group of clinically and genetically heterogeneous disorders with multiple genetic loci participating in its pathogenesis. Here we report three Iranian patients with HSP. Molecular analyses revealed that they have mutations in AP4M1 gene (NM_004722:c.802C>T, p.R268X and c.1225T>C, p.F409L) and AP4E1 gene (NM_007347: c.3212_3213delCT, p.L1072Afs*10). All of them were born to consanguineous parents. Genetic diagnosis was performed using whole exome sequencing (WES), Sanger sequencing and segregation analysis. Due to heterogeneity in clinical manifestations and inheritance mode as well as the presence of different causative genes in HSP, WES facilitates the diagnosis and provides opportunity for prenatal diagnosis in families with affected members.

Clothianidin is a neonicotinoid insecticide that acts as a full agonist stimulating nAChRs and is widely used to control the brown planthopper, Nilaparvata lugens (Stal). To investigate the adaptation of N. lugens in the process of developing resistance to clothianidin, a clothianidin-resistant N. lugens strain and an unselected strain were used in this study. The F1 reciprocal crosses between the resistant and the susceptible strains indicated that the observed resistance was autosomal and incompletely dominant. Chi-square analyses of self-bred and backcrossed progenies suggested that the observed resistance was controlled by multiple genes. The resistant strain exhibited a relative fitness of 0.78 with a significantly increased adult preoviposition period and significantly decreased total fecundity. The current study provides valuable information for resistance management strategies to delay the development of clothianidin resistance in N. lugens.

Recent advances in next‐generation sequencing (NGS) have given rise to new challenges due to the difficulties in variant pathogenicity interpretation and large dataset management, including many kinds of public population databases as well as public or commercial disease‐specific databases. Here, we report a new database development tool, named the “Clinical NGS Database,” for improving clinical NGS workflow through the unified management of variant information and clinical information. This database software offers a two‐feature approach to variant pathogenicity classification. The first of these approaches is a phenotype similarity‐based approach. This database allows the easy comparison of the detailed phenotype of each patient with the average phenotype of the same gene mutation at the variant or gene level. It is also possible to browse patients with the same gene mutation quickly. The other approach is a statistical approach to variant pathogenicity classification based on the use of the odds ratio for comparisons between the case and the control for each inheritance mode (families with apparently autosomal dominant inheritance vs. control, and families with apparently autosomal recessive inheritance vs. control). A number of case studies are also presented to illustrate the utility of this database.

A temperament gene and its inheritance mechanisms have never been academically addressed. In this study we have tried to explain a genetic basis of a temperament inheritance mode; temperament is regularly inherited by the son from the mother and by the daughter from the father. Such a transmission mode corresponds to the X chromosome-linked inheritance and indicates that a temperament gene locus is on the X chromosome. Here we show that most probable temperament gene candidate is the VAMP7 gene of Xq PAR; besides its role in neuritogenesis, a relationship was proposed between the outward migration mode of the VAMP7 mediated vesicles, the female paternal temperament allele preservation in the secondary oocyte/ovum, and its transmission to the next generation. We have eliminated 113 temperament gene candidates in the distal Xq region, due to their mRNA numbers, expression in the brain and ovary, accordance to our proposed inheritance mode of a silent temperament allele, and genetic linkages.

The mutation rate is a fundamental factor in evolutionary genetics. Recently, mutation rates were found to be strongly reduced at high density in a wide range of unicellular organisms, prokaryotic and eukaryotic. Independently, cell division was found to become more asymmetrical at increasing density in diverse organisms; some ‘mother’ cells continue dividing, while their ‘offspring’ cells do not divide further. Here, we investigate how this increased asymmetry in cell division at high density can be reconciled with reduced mutation-rate estimates. We calculated the expected number of mutant cells due to replication errors under various modes of segregation of template-DNA strands and copy-DNA strands, both under symmetrical (exponential) and asymmetrical (linear) growth. We show that the observed reduction in the mutation rate at high density can be explained if mother cells preferentially retain the template-DNA strands, since new mutations are then confined to non-dividing daughter cells, thus reducing the spread of mutant cells. Any other inheritance mode results in anincreasein the number of mutant cells at higher density. The proposed hypothesis that patterns of DNA-strand segregation are density-dependent fundamentally challenges our current understanding of mutation-rate estimates and extends the distinction between germline and soma to unicellular organisms.

BackgroundGenetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified. We aimed to systematically investigate these genes to better understand ataxia pathophysiology.MethodsA manually curated catalogue of 71 genes involved in disorders with progressive ataxias as a major clinical feature was subjected to an integrated gene ontology, protein network and brain gene expression profiling analysis.ResultsWe found that genes mutated in ataxias operate in networks with significantly enriched protein connectivity, demonstrating coherence on a global level, independent of inheritance mode. Moreover, elevated expression specifically in the cerebellum predisposes to ataxia. Genes expressed in this pattern are significantly over-represented among genes mutated in ataxia and are enriched for ion homeostasis/synaptic functions. The majority of genes mutated in ataxia, however, does not show elevated cerebellar expression that could account for region-specific degeneration. For these, we identified defective cellular stress responses as a major common biological theme, suggesting that the defence pathways against stress are more critical to maintain cerebellar integrity than integrity of other brain regions. Approximately half of the genes mutated in ataxia, mostly part of the stress module, show higher expression at embryonic stages, which argues for a developmental predisposition.ConclusionGenetic defects in ataxia predominantly affect neuronal homeostasis, to which the cerebellum appears to be excessively susceptible. Based on the identified modules, it is conceivable to propose common therapeutic interventions that target deregulated calcium and reactive oxygen species levels, or mechanisms that can decrease the harmful downstream effects of these deleterious insults.

Chorea-acanthocytosis (ChAc) is a rare neurodegenerative movement disorder with variable clinical features, including movement disorders, cognitive decline, myopathy, neuropathy, behavioral changes, seizures and acanthocytosis. The majority of ChAc patients display an autosomal recessive mode of inheritance. A pseudodominant way of transmission represents only a rare condition. Few studies have reported the clinical status of the obligate carriers of ChAc. Here, we describe a Chinese ChAc family with a novel mutation in the VPS13A gene, presenting a pseudo-dominant inheritance mode. Our report further expanded the knowledge of phenotypes of ChAc.

Background Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES). Methods Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification. Results All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology. Conclusions Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations. Electronic supplementary material The online version of this article (10.1186/s12967-018-1522-7) contains supplementary material, which is available to authorized users.

m.3243A>G MT-TL1 mutation is the most common mitochondrial DNA mutation that results in a wide spectrum of disorders in a maternally inherited pedigree. In adult patients, many present with symptoms and signs indistinguishable from acquired diseases and the correct diagnosis is often delayed after many years. Nevertheless, clues suggesting m.3243A>G usually exist early in the disease course but are only realized late. These hints, from the evolution of symptoms and signs, family background, investigation results, or a combination of these, enable the physician to make the correct diagnosis early, which is important for appropriate treatment and better patient care. As with other inheritable diseases, genetic counselling should be offered regarding the disease management, inheritance mode, recurrence risk, usefulness and limitations of genetic testing and reproductive options.

International audience; Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

The difference in virulence of two standard strains in colonizing seedling hypocotyle and fruit exocarp suggested thatmulti-locus control of this trait. Whereas, Strain ATCC18099 was unable to infect uninjured cucumber and Zucchini fruits, both strains had high virulence against seedlings. The inheritance mode of this trait was studied by tetrad and random ascospore analysis with ascospores obtained from reciprocal crossings between ATCC18098 and ATCC18099. Segregation of MAT and perithecial color was also examined in both types of ascospore analyses. The results of tetrad analysis indicated 4:4 segregation for the high virulence associated with strain ATCC18098 in each tetrad, suggesting a Mendelian mode of inheritance. In random ascospore analysis, chi-square test supported that progeny with and without high virulence segregated in 1:1 in each cross and linkage analysis showed that such trait segregated independently from either MAT or perithecial color trait.

Imidacloprid, a post-synaptic, nicotinic insecticide, has been commonly used for the management of different pests including Musca domestica worldwide. Many pests have developed resistance to this insecticide. A 16-fold imidacloprid-resistant population of M. domestica infesting poultry was selected using imidacloprid for 13 continuous generations to study the inheritance and realized heritability of resistance. Toxicological bioassay at G14 showed that the imidacloprid-selected population developed 106-fold resistance when compared to the susceptible population. Reciprocal crosses of susceptible and resistant populations showed an autosomal trait of resistance to imidacloprid in M. domestica. There was incompletely recessive resistance in F1 (Imida-SEL ♂ × Susceptible ♀) and F1(†) (Imida-SEL ♀ × Susceptible ♂) having dominance value 0.53 and 0.31, respectively. Monogenic model of inheritance showed that imidacloprid resistance was controlled by multiple factors. The realized heritability value was 0.09 in the imidacloprid-selected population of M. domestica. It was concluded that imidacloprid resistance in M. domestica was autosomally inherited, incompletely recessive and polygenic. These findings should be helpful for better and more successful management of M. domestica.

Motivation: Recent studies on human disease have revealed that aberrant interaction between proteins probably underlies a substantial number of human genetic diseases. This suggests a need to investigate disease inheritance mode using interaction, and based on which to refresh our conceptual understanding of a series of properties regarding inheritance mode of human disease. Results: We observed a strong correlation between the number of protein interactions and the likelihood of a gene causing any dominant diseases or multiple dominant diseases, whereas no correlation was observed between protein interaction and the likelihood of a gene causing recessive diseases. We found that dominant diseases are more likely to be associated with disruption of important interactions. These suggest inheritance mode should be understood using protein interaction. We therefore reviewed the previous studies and refined an interaction model of inheritance mode, and then confirmed that this model is largely reasonable using new evidences. With these findings, we found that the inheritance mode of human genetic diseases can be predicted using protein interaction. By integrating the systems biology perspectives with the classical disease genetics paradigm, our study provides some new insights into genotype–phenotype correlations. Contact: haodapeng@ems.hrbmu.edu.cn or biofomeng@hotmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Castor (Ricinus communis L.) is an important industrial oilseed crop grown worldwide. Wilt caused by Fusarium oxysporum f.sp. ricini is a devastating disease in castor. The inheritance mode of wilt resistance was investigated. The F1, F2 and backcross generations of four crosses involving four resistant and three susceptible parents were developed. The role of digenic (R1 and R2) epistatic interactions on wilt resistance was confirmed. The 15 : 1, 9 : 7 and 13 : 3 ratios indicated duplicate dominant, duplicate recessive and dominant and recessive epistatic interactions, respectively. Castor parents used in the crosses exhibited varied inheritance modes. All generations of a cross exhibited similar inheritance mode when parents were comparable. However, generations varied in inheritance mode when parents were not comparable in inheritance mode. These results would have practical interest when decisions are required regarding the choice of parents and methodology in resistance and hybrid breeding. The results also provided a basis for investigating molecular genetics of wilt resistance mechanisms.

Introduction. Familial aggregation of ankylosing spondylitis (AS) has been frequently noticed. However, the mode of inheritance in AS remains poorly understood. Our aim was to determine the mode of inheritance best fitting the observed transmission pattern of AS families. Methods. Families with 5 or more AS patients diagnosed with 1984 modified New York criteria were recruited. We performed complex segregation analysis for a binary trait in regressive multivariate logistic models. The inheritance models, including sporadic, major gene, environmental, general, and other 9 models, were compared by likelihood ratio tests and Akaike’s Information Criterion. Results. This research included 9 Chinese Han AS families with a total number of 315 persons, including 74 patients. First, familial association was determined. Sporadic with familial association model was rejected when compared with either the general model or the homogeneous general model (p<0.001). The environmental model was also rejected when compared with general models (p<0.02). Mendelian dominate mode fitted best in 5 AS families, while Tau AB free model best explained the mode of inheritance in these AS families. Conclusion. This study provided evidence in support of Mendelian dominant mode and firstly discovered a non-Mendelian mode called tau AB free inheritance mode in AS.

In the endangered Scottish chough (Pyrrhocorax pyrrhocorax) population, a lethal blindness syndrome is found to be caused by a deleterious recessive allele. Photo: Gordon Yates. In Focus: Trask, A.E., Bignal, E.M., McCracken, D.I., Monaghan, P., Piertney, S.B. & Reid, J.M. (2016) Evidence of the phenotypic expression of a lethal recessive allele under inbreeding in a wild population of conservation concern. Journal of Animal Ecology, 85, 879-891. In this issue of Journal of Animal Ecology, Trask et al. () report on a strange, lethal, blindness that regularly affects chicks of an endangered bird population. The authors show that the inheritance mode of this blindness disease precisely matches the expectations of a recessive deleterious mutation. Intriguingly, there is also an indication that the disease-causing variant might be maintained in the population by balancing selection, due to a selective advantage for heterozygotes. Could this finding have consequences for conservation actions implemented for the population?

‘Yuntian-930’ is a wild melon that is highly resistant to powdery mildew (PM). To determine the inheritance of resistance to powdery mildew (PM), ‘Yuntian-930’ was crossed with another cultivated melon, ‘Hualaishi’, which is susceptible to PM. Inheritance of resistance to Podosphaera xanthii race 2F. in six plant generations (P1, P2, F1, B1, B2, and F2) was studied using the mixed major-gene plus polygene inheritance mode with joint analysis method. Inheritance of resistance in wild melons fitted the model of two pairs of additive-dominance-epitasis major genes plus additive-dominant-epitasis polygene. The additive, dominant, and epistatic effects between the two major genes played an important role in inheritance. The estimated values of heritability of major genes in B1, B2, and F2 were 62.98, 58.58 and 90.89%, and those of polygene heritability were 28.93, 31.47 and 3.22%, respectively. The ratios of the environmental variance to phenotype variance were 5.89-9.94%. Thus, resistance of ‘Yuntian-930’ to PM was controlled not just by two major genes, but was also affected by polygene and the environment. The selection efficiency for a major gene of F2 was highest in the resistance breeding program.

Musca domestica Linnaeus (house fly, Diptera: Muscidae) is a major veterinary and medical important pest all over the world. These flies have ability to develop resistance to insecticides. The present trial was performed to discover the inheritance mode (autosomal, dominance, number of genes involved) and preliminary mechanism of methoxyfenozide resistance in order to provide basic information necessary to develop resistance management strategy for this pest. A strain of M. domestica (MXY-SEL) was exposed to methoxyfenozide for 44 generations which developed a 5253.90-fold level of resistance to methoxyfenozide. The overlapping fiducial limits of LC50 values of the reciprocal crosses, F1 (MXY-SEL ♂ × Susceptible ♀) and F1† (MXY-SEL ♀ × Susceptible ♂), suggest that inheritance of methoxyfenozide resistance was an autosomal and likely completely dominant trait (DLC = 0.93 and 0.94 for F1 and F1†, respectively). Backcrosses of the F1 with the parental MXY-SEL or Susceptible population predict a polygenic mode of inheritance. Piperonyl butoxide significantly altered the LC50 values, suggesting enhanced detoxification by cytochrome P450-dependent monooxygenases is a major mechanism of resistance to methoxyfenozide in the MXY-SEL strain. The estimated realized heritability was 0.07 for methoxyfenozide. These results would be helpful for the better management of M. domestica.

Aim: To evaluate the inheritance mode of aggressive periodontitis in a collection of families with a similar geographic origin. Materials and Methods: Segregation analysis was performed in pedigree data from 74 families by the use of the SEGREG program of SAGE v.5.4.2. Homogeneous no transmission, homogeneous Mendelian transmission, homogeneous general transmission, semi-general transmission and heterogeneous general transmission models were tested assuming the prevalence of aggressive periodontitis as 1% and no deviations from Hardy-Weinberg equilibrium. The parameters of the model were estimated by the method of maximum likelihood, which provides the overall ln (likelihood), -2ln and the AIC (Akaike's score) for each model. The likelihood ratio test (LRT) was used to compare each model against a fully general model (p>0.05). Results: The most parsimonious mode of inheritance was the semi-general transmission model that allows the heterozygote transmission probability to vary. Conclusion: This result provides strong support for the hypothesis that genetic factors play a role in aggressive periodontitis and that a few loci, each with relatively small effects, contribute to aggressive periodontitis, with or without interaction with environmental factors. © 2009 John Wiley & Sons AS.

The inheritance mode of seven microsatellite markers was investigated in Patinopecten yessoensis larvae from four controlled crosses, and the feasibility of using these markers for kinship estimation was also examined. All the seven microsatellite loci were compatible with Mendelian inheritance. Neither sex-linked barriers to transmission nor major barriers to fertilization between gametes from the parents were evident. Two of the seven loci showed the presence of null alleles in two families, suggesting the need to conduct comprehensive species-specific inheritance studies for microsatellite loci used in population genetic studies. However, even if the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from four families were all unambiguously discriminated in the neighbor-joining dendrogram. This result indicates that the microsatellite markers used may be capable of discriminating between related and unrelated scallop larvae in the absence of pedigree information, and of investigating the effective number of parents contributing to the hatchery population of the Japanese scallop.

Five full-sib families of the Pacific oyster (Crassostrea gigas) larvae were used to study the mode of inheritance at eight microsatellite loci, and the feasibility of these markers for kinship estimate was also examined. All eight microsatellite loci were compatible with Mendelian inheritance. Neither evidence of sex-linked barriers to transmission nor evidence of major barriers to fertilization between gametes from the parents was shown. Three of the eight loci showed the presence of null alleles in four families, demonstrating the need to conduct comprehensive species-specific inheritance studies for microsatellite loci used in population genetic studies. Although the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from five full-sib families were unambiguously discriminated in the neighbor-joining dendrogram. This result indicates that the microsatellite markers may be capable of discriminating between related and unrelated oyster larvae in the absence of pedigree information, and is applicable to the investigation of the effective number of parents contributing to the hatchery population of the Pacific oyster.

Motivation: Exome sequencing studies have facilitated the detection of causal genetic variants in yet-unsolved Mendelian diseases. However, the identification of disease causal genes among a list of candidates in an exome sequencing study is still not fully settled, and it is often difficult to prioritize candidate genes for follow-up studies. The inheritance mode provides crucial information for understanding Mendelian diseases, but none of the existing gene prioritization tools fully utilize this information. Results: We examined the characteristics of Mendelian disease genes under different inheritance modes. The results suggest that Mendelian disease genes with autosomal dominant (AD) inheritance mode are more haploinsufficiency and de novo mutation sensitive, whereas those autosomal recessive (AR) genes have significantly more non-synonymous variants and regulatory transcript isoforms. In addition, the X-linked (XL) Mendelian disease genes have fewer non-synonymous and synonymous variants. As a result, we derived a new scoring system for prioritizing candidate genes for Mendelian diseases according to the inheritance mode. Our scoring system assigned to each annotated protein-coding gene (N = 18 859) three pathogenic scores according to the inheritance mode (AD, AR and XL). This inheritance mode-specific framework achieved higher accuracy (area under curve = 0.84) in XL mode. Conclusion: The inheritance-mode specific pathogenicity prioritization (ISPP) outperformed other well-known methods including Haploinsufficiency, Recessive, Network centrality, Genic Intolerance, Gene Damage Index and Gene Constraint scores. This systematic study suggests that genes manifesting disease inheritance modes tend to have unique characteristics. Availability and implementation: ISPP is included in KGGSeq v1.0 (http://grass.cgs.hku.hk/limx/kggseq/), and source code is available from (https://github.com/jacobhsu35/ISPP.git). Contact: mxli@hku.hk Supplementary information: Supplementary data are available at Bioinformatics online.

In early 2015, the debate of blue-black and white-gold color perception from “the dress” became an overnight internet phenomenon. According to the vote from the online social network Twitter, more people observed white-gold colors than those who observed blue-black colors. Biological explanations have been proposed by neurologist and other scientists, most of which mainly focus on the bias of color perception from visual cortex assuming different illuminants as backgrounds. The goal of this study was to investigate the genetic reason that might be underlying this phenomenon. We carried out a preliminary survey study using four complex pedigrees and examined the inheritance mode influencing the ability to perceive the real colors, blue-black, from the photograph. We evaluated the likelihood of sporadic, major gene in Mendelian mode, major gene in non-Mendelian mode and environmental models. Complex segregation analyses indicated that the inheritance was probably due to a non-Mendelian major gene effect. Our study also indicated the importance of environmental or epigenetic factors in this color perception trait.

Motivation: With the knowledge of large number of SNPs in human genome and the fast development in high-throughput genotyping technologies, identification of linked regions in linkage analysis through allele sharing status determination will play an ever important role, while consideration of recombination fractions becomes unnecessary.Results: In this study, we have developed a rule-based program that identifies linked regions for underlined diseases using allele sharing information among family members. Our program uses high-density SNP genotype data and works in the face of genotyping errors. It works on nuclear family structures with two or more siblings. The program graphically displays allele sharing status for all members in a pedigree and identifies regions that are potentially linked to the underlined diseases according to user-specified inheritance mode and penetrance. Extensive simulations based on the χ2 model for recombination show that our program identifies linked regions with high sensitivity and accuracy. Graphical display of allele sharing status helps to detect misspecification of inheritance mode and penetrance, as well as mislabeling or misdiagnosis. Allele sharing determination may represent the future direction of linkage analysis due to its better adaptation to high-density SNP genotyping data.Availability: http://paed.hku.hk/uploadarea/yangwl/html/index.htmlContact: yangwl@hkucc.hku.hkSupplementary information: Supplementary data are available at Bioinformatics online.

Microsatellite markers can provide information on the family structure and genetic diversity based on legible co-dominant Mendel inheritance fashion in diploids. However, parentage and genetics analysis of sturgeon using microsatellite markers is complicated by the polyploidy nature of the species. In the present study, the inheritance mode of microsatellite loci is shown using 3 families created from wild Chinese sturgeon ( Acipenser sinensis). Primers As-073, Spl-168, and As-100 indicated a maximum of four even-intensity bands per individual and pairwise combination of alleles segregation in the progeny that fit tetrasomic inheritance ( P > 0.05). Double reduction exhibited at As-073 simultaneously gave evidence of tetrasomic inheritance. The mode of inheritance at As-074 and Afu-54, both expressing more than two alleles in one individual, could not be ultimately determined because of few inheritance data. The occurrence of null allele at Spl-168 and As-074 was noted.

Objectives To present the prenatal genetic diagnoses and counseling for two cases of oculocutaneous albinism (OCA) type I family by detection of mutations in the OCA1 gene by denaturing high performance liquid chromatography (DHPLC) system and a review of the literature. Methods All DNA samples were extracted from peripheral whole blood and amniocentesis-derived cells. Mutation analysis was performed for all five coding exons of the TYR gene, which were amplified by PCR. DHPLC was used for heteroduplex detection and sequence analysis was performed to demonstrate the mutation loci. Results Case 1: After sampling of blood from the family members and performing amniocentesis of the fetus, it was demonstrated that the affected boy and the female fetus were shown to be compound heterozygotes for mutations in the TYR gene. In addition, it was shown that the parents were carriers of the two mutations. However, the couple chose to keep the baby. Case 2: Mutation analysis of the DNA of the siblings revealed two heterozygous mutations in the TYR gene. Her husband is free of the disease. According to the principles of autosomal recessive inheritance, the incidence of affected offspring is very low. Conclusions Herein we introduce a novel application for molecular diagnostic of DHPLC coupled with direct sequencing, which can provide an effective and exact diagnosis in patients with albinism. Clinicians should be cognizant of the risk of OCA inheritance by the offspring through careful identification of genetic mutations and the inheritance mode, both important to ensure comprehensive genetic counseling. Copyright © 2006 John Wiley & Sons, Ltd.

Productive tillering is a very important trait which influences the degree of barley lodging resistance. Five dive-gent genotypes of two-rowed winter barley (Vada, Djerdap, NS-293, Jagodinac and Sladoran) have been selected for diallel crossing in order to study the mode of inheritance, the gene effect and the components genetic variance for the productive tillering in F1 and F2 generation. The test of the significance of the generations' mean values related to the parental average was used for inheritance mode determinations (KRALJEVIC-BALALIC et al., 1991) and the genetic variance components and regression VrWr analysis from diallel crossings were made using the method of MATHER and JINKS (1971). The variability of the investigated trait differed. The cross combination Djerdap x Jagodinac had the highest coefficient of variance (39.78%). Different modes of inheritance (partial dominance, dominance and over dominance) and partial dominance were found in the F1 and F2 generation, respectively. The genetic variance components, average degree of dominance and regression line indicated partial dominance in the inheritance of tillering. The range of the obtained values of heritability for the tillering was found to be very wide (0.02-0.47). The cross combinations Djerdap x Jagodinac and Vada x Djerdap were selected for future breeding.

229 SSRs (simple sequence repeats) were identified among 10,443 ESTs (expressed sequence tags) of Chinese shrimp (Fenneropenaeus chinensis). The average density of SSRs was one SSR per 19.1 kb of EST sequence screened. The dinucleotide repeats appeared to be the most abundant SSRs detected. Nine EST-SSR markers were detected polymorphisms of the thirty SSR primer pairs derived from F. chinensis ESTs. The number of alleles per locus ranged from 5 to 15, with an average of 9.1 alleles per locus. The observed heterozygosity of nine loci ranged from 0.47 to 0.87. These loci were used successfully for pedigree analysis in three families of Fenneropenaeus chinensis. Two of the nine microsatellite loci showed the existence of null alleles. Assuming the existence of null alleles at Fc07 and Fc14 loci, the allelic inheritance mode of the EST-SSR DNA markers (Fc04, Fc06, Fc07, Fc10, Fc14, Fc18, Fc22, Fc24, and Fc27) was consistent with Mendelian segregation.

A separation of the effects of major genes from effects of polygenes is important to understand genetic inheritance of quantitative traits and predict the segregation of a crossing. The inheritance mode of resistance to anthracnose leaf bligh t (ALB) caused by C. graminicola was evaluated by a mixed model. P 1, P2, F1, F2, BC1, and BC2 generations derived from four crossings between tropical maize inbred lines were used. Maximum likelihood was used to choose the best fitting inheritance model and to estimate genetic parameters. The mixed model indicated that the resistance to ALB was controlled by a major gene in all crosses and trials, and by polygenes in at least one trial. Additive and dominance effects were important for both major gene and polygenes. Both effects of the major genes were negative, indicating their contribution to disease resistance, while both effects of the polygenes were positive or negative, reflecting differences in the genetic background among inbred li nes.

The inheritance mode of six previously published and newly developed microsatellite markers was investigated in newly hatched Haliotis discus hannai larvae from four controlled crosses, and the feasibility of these markers for kinship estimation was also examined. Microsatellite DNA was successfully amplified from H. discus hannai larvae using the Chelex extraction method, and at least 15 microsatellite loci could be analyzed in a single trochophore larva. All six microsatellite loci were compatible with Mendelian inheritance. Neither evidence of sex-linked barriers to transmission nor evidence of major barriers to fertilization between gametes from the parents was shown. One of the six microsatellite loci showed the existence of null alleles in one family, indicating that the loci should be used in population studies with caution. Although the null allele heterozygotes were considered as homozygotes in the calculation of genetic distance, offspring from four full-sib families were unambiguously discriminated in the neighbor-joining dendrogram. The result demonstrates that the microsatellite markers might be capable of discriminating between related and unrelated abalone larvae in the situation where no pedigree information is available.

Mature pollen grains of 295 angiosperm species were screened by epifluorescence microscopy for a marker that denotes the mode of cytoplasmic inheritance. We used the DNA fluorochrome DAPI (4',6-diamidino-2-phenylindole) for pollen cell staining. The presence or absence of fluorescence of cytoplasmic DNA in the generative cell or sperm cells was examined in each species. The species examined represented 254 genera and 98 families, and 40 of these families had not been previously studied in this regard. The cytoplasmic DNA of the generative cell or sperm cells did not fluoresce in 81% of the species examined, from 83% of the genera and 87% of the families examined, indicating the potential for maternal cytoplasmic inheritance in these species. In contrast, the male reproductive cells of 19% of the species, from 17% of the genera and 26% of the families examined, displayed fluorescence of the cytoplasmic DNA, indicating the potential for biparental cytoplasmic inheritance in these species. The results revealed the potential for biparental cytoplasmic inheritance in several species in which the inheritance mode was previously unknown, including plants in the Bignoniaceae, Cornaceae, Cruciferae (Brassicaceae), Cyperaceae, Dipsacaceae, Hydrocharitaceae, Papaveraceae, Portulacaceae, Tiliaceae, Valerianaceae, and Zingiberaceae. Electron microscopy revealed that the sperm cells of Portulaca grandiflora contain both plastid and mitochondrial DNA. However, in the generative cells of Musella lasiocarpa, the mitochondria contain DNA, but the plastids do not. These data provide a foundation for further studies of cytoplasmic inheritance in angiosperms.

We investigated the shape of tomato fruit by evaluating the ratio between the horizontal and vertical diameter in diallele crossings of 6 parental genotypes (D-150, S-49, S-35 and H-52, Kg-z and SP-109). The diallele and their progeny (F1, F2, BC1 and BC2), were used to investigate the mode of inheritance by generation mean analysis (Mather and Jinks, 1982). Additive gene effects were the most significant in affecting the inheriting the fruit shape. Most frequently expressed epistatic effects were the additive x dominance interaction, followed by additive x additive gene effects. The duplicate type of epistasis was relatively stable.

The existence of a sorghum (Sorghum bicolor Moench) thermo-sensitivity gene has been proposed to account for the acceleration of flower initiation when plants are exposed to a temperature lower than 20°C. Four varieties and their F1, F2, F3 and BC1F1 populations were evaluated for days to emergence of flag leaf (DEFL) under the field condition of a long daylength (> 13 h) and temperatures over 20°C for at least 40 days after sowing. The F1 hybrids, Hiromidori (Norin Ko-2) : 390 (early) × Regs.Hegari (late) and Natsuibuki (Norin Ko-9) : MS175 (late) × Daikoukaku (early), showed the same flowering response as Regs.Hegari and MS175 which show a delay in DEFL under temperatures over 20°C, suggesting the presence of a dominant thermo-sensitivity gene. In two different F2 populations, the segregation of early and late plants for DEFL fitted in with the expected ratio of 1 : 3, indicating that a single dominant gene was controlling the phenotype. The inheritance mode was confirmed in two different BC1F1 populations, where the expected ratio of 1 : 1 (early : late) was observed in the segregation of BC1F 1 of 390 × F1 and F1 × Daikoukaku. As expected, no segregation was observed in BC1F1 populations of F1 × Regs.Hegari and MS175 × F1. These results suggest that the sorghum thermo-sensitivity for flower initiation is controlled by a monogenic dominant gene of late over early, and the symbol TT is assigned to the genotype in which flower initiation is accelerated by the exposure to a temperature lower than 20°C.

To study the inheritance mode of hexaploid chrysanthemum (random or preferential chromosome pairing), a segregation analysis was carried out using SSR markers derived from chrysanthemum ESTs in the public domain. A total of 248 EST-SSR primer pairs were screened in chrysanthemum cultivars ‘Dancer’ and ‘Puma White’, of which 49 EST-SSRs were selected as polymorphic and informative markers. These polymorphic markers were used for genotyping a F 1 -pseudo test cross population derived from a cross between these two cultivars. The 49 EST-SSRs detected 210 marker alleles with an average number of 4.29 marker alleles per locus. For 180 of these polymorphic SSR marker alleles, segregation could be estimated using a χ 2 goodness of fit test ( α = 0.05) with the expected segregation ratios for hexasomic or disomic inheritance. For 65 SSR marker alleles the segregation ratio was informative for the type of inheritance, 33 marker alleles gave a good fit to the expected segregation ratio for hexasomic inheritance and whereas 24 marker alleles gave a good fit for disomic inheritance showing a higher number of marker alleles supporting autopolyploid segregation in chrysanthemum. In addition, the observed ratio of non-simplex to simplex markers was 20:80 (25 vs. 99) supported hexasomic inheritance. Furthermore, random marker allele assortment was found within the six fully informative markers giving conclusive evidence for hexasomic inheritance in chrysanthemum at these chromosomal regions.

The allelic inheritance mode of microsatellite DNA markers was examined using seven copulated wild females and their offspring. Five microsatellite loci, CSPJ002*, CSPJ010*, CSPJ012*, CSPJ014*, and CSPJ015*, were used in the study. At almost all family/locus combinations, one sire was determined and distributions of genotypes in offspring were consistent with the Mendelian segregation ratio. Distributions of genotypes were consistent with the ratio after assuming a null allele at some loci. Consequently, the alleles of CSPJ002* and CSPJ012* were inherited following the Mendelian inheritance mode in every family; however, the null allele was expected in CSPJ010*, CSPJ014*, and CSPJ015* in some families. Thus, these loci should be used carefully in population genetic analysis, but siblings could be detected in the dendrograms based on unweighted pair-group method using arithmetic averages (UPMGA).

We report on rare, heritable, permanent tooth agenesis in a large Chinese kindred. The congenital absence of permanent teeth except the first and second accessory teeth was observed in 52 individuals through six successive generations in the kindred comprising 328 members. Clinical assessments were carried out, and inheritance mode and spousal influence of the anomaly on their offspring were analyzed. Consequently, the anomaly was transmitted in an autosomal dominant fashion with incomplete penetrance (P = 0.88), and no significant clinical manifestations other than the oligodontia were found. A geographical or environmental effect on the affected individuals was obviously eliminated, because any who are related to the kindred but live under the same conditions are fully healthy. The disorder we describe, therefore, differs from any previously reported oligodontia/anodontia syndromes. The oligodontia ranged from a few teeth to the whole set of teeth, and usually occurred at a period from age 7 or 8 years, the time when primary teeth are normally replaced by permanent teeth, to the forties. Roentgenography of the affected persons indicated that only the first and/or second accessory teeth with tooth buds developed as permanent teeth. In fact, the diphyodontic germination sometimes occurred in the oral cavity of the affected individuals.

A spontaneous morphological mutation characterized by a short and kinky tail (Tail-short Shionogi: Tss) was observed in a BALB/cMs mouse breeding colony. The inheritance mode of the Tss mutation is semi-dominant, and homozygotes (Tss/Tss) are probably embryonic lethal. The viability of the Tss/+ heterozygotes appear to be influenced by the mating partner: 47.1% of the (BALB/cMs-Tss/+ x C57BL/6J)F1 embryos were the mutant phenotype, whereas there were no (BALB/cMs-Tss/+ x A/J)F1 embryos with the mutant phenotype. The Tss locus was mapped by linkage analysis between microsatellite markers D11Mit128 and D11Mit256 on mouse Chromosome 11. These results suggest that the Tss mutation is a new allele on the Tail-short (Ts) locus.

The genetic factors involved in the sexual isolation between Drosophila simulans females and D. melanogaster males are hardly known. We present a study of female mating propensity of D. simulans from different geographic origins with D. melanogaster males. Our results reveal the existence of genetic variability in D. simulans for this trait. Female discrimination is dominant against high female interspecific mating, which differs from that detected in other Drosophila species crosses.