Mendelian Character Research Articles

A structural variant in the 5'-flanking region of the TWIST2 gene affects melanocyte development in belted cattle.

Belted cattle have a circular belt of unpigmented hair and skin around their midsection. The belt is inherited as a monogenic autosomal dominant trait. We mapped the causative variant to a 37 kb segment on bovine chromosome 3. Whole genome sequence data of 2 belted and 130 control cattle yielded only one private genetic variant in the critical interval in the two belted animals. The belt-associated variant was a copy number variant (CNV) involving the quadruplication of a 6 kb non-coding sequence located approximately 16 kb upstream of the TWIST2 gene. Increased copy numbers at this CNV were strongly associated with the belt phenotype in a cohort of 333 cases and 1322 controls. We hypothesized that the CNV causes aberrant expression of TWIST2 during neural crest development, which might negatively affect melanoblasts. Functional studies showed that ectopic expression of bovine TWIST2 in neural crest in transgenic zebrafish led to a decrease in melanocyte numbers. Our results thus implicate an unsuspected involvement of TWIST2 in regulating pigmentation and reveal a non-coding CNV underlying a captivating Mendelian character.

Mapping of new resistance (Vr2, Rm1) and ornamental (Di2, pl) Mendelian trait loci in peach

Peach powdery mildew is one of the major diseases of the peach. Various sources of resistance to PPM have thus been identified, including the single dominant locus Vr2 carried by the peach rootstock ‘Pamirskij 5’. To map Vr2, a linkage map based on microsatellite markers was constructed from the F2 progeny (WP2) derived from the cross ‘Weeping Flower Peach’ × ‘Pamirskij 5’. Self-pollinations of the parents were also performed. Under greenhouse conditions, all progenies were scored after artificial inoculations in two classes of reactions to PPM (resistant/susceptible). In addition to Vr2, WP2 segregated for three other traits from ‘Weeping Flower Peach’: Rm1 for green peach aphid resistance, Di2 for double-flower and pl for weeping-growth habit. With their genomic locations unknown or underdocumented, all were phenotyped as Mendelian characters and mapped: Vr2 mapped at the top of LG8, at 3.3 cM, close to the CPSCT018 marker; Rm1 mapped at the bottom of LG1, at a position of 116.5 cM, cosegregating with the UDAp-467 marker and in the same region as Rm2 from ‘Rubira’®; Di2 mapped at 28.8 cM on LG6, close to the MA027a marker; and pl mapped at 44.1 cM on LG3 between the MA039a and SSRLG3_16m46 markers. Furthermore, this study revealed, for the first time, a pseudo-linkage between two traits of the peach: Vr2 and the Gr locus, which controls the red/green color of foliage. The present work therefore constitutes a significant preliminary step for implementing marker-assisted selection for the four major traits targeted in this study.

T49 - Comorbidity Of Multiple-Factor And Hereditary Diseases In Families: Contribution To Schizophrenia Genetics

Background The comparative role of heredity in the etiology of schizophrenic disorders is estimated as 60-70%, other 30-40% is the share of the environment. However, modern molecular-genetic technologies, including full-genomic, are not able to explain more than 10-15% of the general hereditary components of this multiple-factor disease. One of the main resources of disclosing missing heritability is connected with the schizophrenia phenotype, study of clinical polymorphism of schizophrenia and comorbid with it hereditary diseases. Methods For 209 families of patients with different forms of schizophrenia (F20 according to ICD-10) by means of the genealogical method family trees with identification of state of mental and physical health of relatives of the first degree of relationship were made. If hereditary diseases being suspected, biochemical investigations with identification of metabolites, molecular-genetic (with testing of genetic polymorphisms) investigations were carried out. Results Identification of the role of genetic factors in developing of diseases of the noninfectious nature to which schizophrenic disorders belong, through detection of associations of such diseases with Mendelian characters in families showed the following. Schizophrenia and hereditary Mendelian recessive disease with disturbance of the gene coding Cu-transporting ATPase - Wilson-Konovalov illness (hepatocerebral dystrophy). Schizophrenia and hereditary Mendelian dominant disease (with complete penetrance and varying expressivity of the gene FBN1 (fibrillin 1) - the peculiar Mass-phenotype of the proband and his relatives in the area of the father. Schizophrenia and Leiden mutation (predisposition to thrombosis, thrombophilia) with molecular-genetic investigation of polymorphism of Arg506Gln in the gene of V factor of coagulation. The heterozygotic carriage (G/A genotype) was found. Schizophrenia with manifestations of the velocardiofacial syndrome and existence of polymorphisms of alleles of Val 158Met and rs4680 of the gene COMT as well as CYP2D6 gene polymorphisms. Discussion For schizophrenic disorders as diseases with family history and blunted phenotype which do not conform Mendelian patterns of inheritance in which complex interaction of many pathogenic genes with environmental factors takes place, identification of comorbid with them hereditary (chromosomal and gene) diseases gives the chance of the differentiated clinical diagnostics, prediction of course and development, treatment and outcome of the disease for the specific patient as well as possibility of primary prevention in families.

Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat

In the inbred SHR/OlaIpcv rat colony, we identified males with small testicles and inability to reproduce. By selectively breeding their parents, we revealed the infertility to segregate as an autosomal recessive Mendelian character. No other phenotype was observed in males, and females were completely normal. By linkage using a backcross with Brown Norway strain, we mapped the locus to a 1.2Mbp segment on chromosome 7, harboring 35 genes. Sequencing of candidate genes revealed a G to A substitution in a canonical 'AG' splice site of intron 37 in Sbf1 (SET binding factor 1, alias myotubularin-related protein 5). This leads to either skipping exon 38 or shifting splicing one base downstream, invariantly resulting in frameshift, premature stop codon and truncation of the protein. Western blotting using two anti-Sbf1 antibodies revealed absence of the full-length protein in the mutant testis. Testicles of the mutant males were significantly smaller compared with SHR from 4weeks, peaked at 84% wild-type weight at 6weeks and declined afterward to 28%, reflecting massive germ cell loss. Histological examination revealed lower germ cell number; latest observed germ cell stage were round spermatids, resulting in the absence of sperm in the epididymis (azoospermia). SBF1 is a member of a phosphatase family lacking the catalytical activity. It probably modulates the activity of a phosphoinositol phosphatase MTMR2. Human homozygotes or compound heterozygotes for missense SBF1 mutations exhibit Charcot-Marie-Tooth disease (manifested mainly as progressive neuropathy), while a single mouse knockout reported in the literature identified male infertility as the only phenotype manifestation.

Hereditary Hypohidrotic Ectodermal Dysplasia: Report of a Rare Case

Hereditary Hypohidrotic Ectodermal Dysplasia (HHED), an X-linked, recessive, Mendelian character, is seen usually in males and it is inherited through female carriers. It is characterised by congenital dysplasia of one or more ectodermal structures and it is manifested by hypohidrosis, hypotrichosis and hypodontia. It results from abnormal morphogenesis of cutaneous and oral embryonic ectoderm. Here, we are presenting a rare case of HHED in a 19 year female with classic features of this condition.

Commentary: Connections between genetics and statistics: a commentary on Fisher's 1951 Bateson lecture--'Statistical Methods in Genetics'

My second formally published paper, written with Peter Parsons and entitled ‘The analogy between factorial experimentation and balanced multi-point linkage tests’, 1 opens with the sentence ‘It was pointed out by Fisher 2 in the Bateson lecture that the factorial method of experimentation, now used extensively in agriculture and other fields of research, derives its name and structure from the simultaneous segregation of Mendelian characters’. As Fisher put it in his lecture, ‘I may mention a connection between our two subjects’, namely genetics and statistics, ‘which seems not to be altogether accidental’. He later says ‘What a beautifully controlled experiment, again, is put into the geneticist’s hands in a linkage test by simple backcross to a multiple recessive. Here each pair of allelomorphic genes should occur, though in different combinations, equally in each of the pairs of complementary genotypes which constitute his results. The first step to perfect control against viability disturbances, is then inherent in his material’. Fisher had defined what he called a ‘balanced’ multipoint linkage test in 1936 as one where there are both coupling and repulsion data for every possible pair of factors. 3 For a simple two-factor test, this would just mean having data from both the coupling (AB/ab ¼ ab/ab) and repulsion (Ab/aB ¼ ab/ab) double heterozygote backcrosses. In a later paper, 4 devoted to analysing a three-point linkage test in the mouse, he advocated using all four possible combinations of heterozygotes (ABC/abc, Abc/aBC, aBc/AbC and abC/ABc) to enable estimation of the recombination frequencies that would take into account the differential viabilities of the various genotypes, while at the same time enabling the estimation of these viability effects. This is clearly what he was referring to in the above quote and which he describes in more detail later in the lecture. In the 1949 paper, he pointed out that the results could be arranged in the form of a latin square, and it was this arrangement that Bodmer and Parsons 1 exploited in their factorial interpretation of such an experiment, something that Fisher must clearly have had in mind.

Phenotypic diversity and relationships of fruit quality traits in peach and nectarine [Prunus persica (L.) Batsch] breeding progenies

Agronomic and fruit quality traits were evaluated and compared for three consecutive years on 1,111 seedlings coming from 15 peach and nectarine breeding crosses, grown under a Mediterranean climate. Significant differences among and within the different progenies were found for most of the traits analyzed. The breeding population segregated for several Mendelian characters such as peach or nectarine fruit, round or flat fruit, yellow or white flesh and freestone or clingstone. In addition, aborting fruit and flat fruit trees were found in our progeny, and our data seem to support multi-allelic control of both flat shape and aborting fruit. The variation within the progenies of some traits such as blooming and harvesting date, yield, fruit weight and SSC was continuous, suggesting a polygenic inheritance. Relationships between qualitative pomological traits and these agronomic and fruit quality parameters were also found. Valuable correlations among agronomic and fruit quality parameters were found, although coefficients of variation depending on the progeny should be considered. In addition, principal component analysis (PCA) revealed several relationships among quality traits in the evaluated progenies. Based on this evaluation, 26 outstanding genotypes were pre-selected from the initial breeding population for further studies.

Ectodermal dysplasia

Hereditary hypohidrotic ectodermal dysplasia, also called the Christ-Siemens-Touraine Syndrome is characterized by congenital dysplasia of one or more ectodermal structures and is manifested by hypohidrosis, hypotrichosis and hypodontia. It is usually an X-linked recessive mendelian character which is rarely seen in males. It results from abnormal morphogenesis of cutaneous and oral embryonic ectoderm. Patients with this disorder exhibit smooth, thin and dry skin, fine and blond scanty hair. Intra-orally anodontia or hypodontia, with impaired development of alveolar process is seen. A case report of a rare case of this disorder in a female patient aged 18 years is hereby presented.

Catch me if you can: tracking down the genetic origins of congenital heart disease

Congenital heart disease (CHD) is the major cause of death in infants under 1 year of age. CHD kills more children than cancer and accounts for 25% of all birth defects, the single largest category of malformations.1 One newborn in 100 has CHD, and 1 newborn in 1000 will need surgery for CHD. Despite the impressive progress which has been made in deciphering the molecular events governing cardiogenesis, only a minority of heart defects are amenable to routine genetic diagnosis at the present time. Thus, the mechanism of disease remains elusive in the majority of patients, and classification and treatment of these malformations are based purely on morphological criteria. Which leads can then be followed to track the genetic basis of CHD? One classic approach, linkage analysis, requires relatively large families segregating the disease trait in a Mendelian fashion. Apart from variable expressivity and reduced penetrance of mutations, which can obscure the Mendelian character of disease, the relative rarity of these families makes their recognition and ascertainment a challenging task ( Table 1 ). Candidate gene approaches have been advocated based on the results of linkage studies, as well as based on the rapidly growing number of candidate genes which play important roles in embryonic heart formation. Clearly, some genotype–phenotype correlations have emerged from these studies—such as those linking mutations in NKX2.5 with atrial septal defects and atrioventricular conduction … *Corresponding author. Tel: +1 514 345 4931 ext 3244; fax: +1 514 345 4896. E-mail address: gregor.andelfinger{at}umontreal.ca

Development of a second-generation genetic linkage map for peach [Prunus persica (L.) Batsch] and characterization of morphological traits affecting flower and fruit

An improved genetic linkage map was constructed from a peach Ferjalou Jalousia® × Fantasia (J×F) F2 population. Ferjalou Jalousia® is a flat low-acidity clingstone peach, and Fantasia is a round, normally acidic freestone peach. This population is segregated for six Mendelian characters: pollen sterility, peach or nectarine fruit, flat or round fruit, clingstone, or freestone fruit. It also segregates for the D major gene controlling the fruit’s low acidity. A new character is reported here for the first time that segregates as a Mendelian character: trees bearing aborting fruits. These trees have flowers, but fruits start to fall 2 months after blooming. This recessive character has been named Af. We demonstrate that it is linked to the flat shape of the fruit. The previous map obtained from this cross was constructed using 63 individuals, whereas the present map was constructed using 207 individuals. Moreover, 82 simple-sequence repeat (SSR) markers, including 10 expressed sequence tag-SSRs, and 43 amplified fragment length polymorphism (AFLP) markers were added. Molecular markers linked to the six Mendelian characters were identified, and one of them has already been used for marker-assisted selection. This map will be used for detection of quantitative trait loci controlling organoleptic and nutritional fruit quality in peach.

Inheritance of growth form and mechanical characters in reciprocal polyploid hybrids of Rosa section Caninae—implications for the ecological niche differentiation and radiation process of hybrid offspring

Within Rosa section Caninae (dogroses) two different growth types exist, arching (L-type) and erect (D-type). Due to the specific mode of chromosome allocation during meiosis, character inheritance in dogroses is maternally skewed. In this paper we try to assess the mode of inheritance of the ‘growth form’ in reciprocal hybrids of R. canina L. and R. rubiginosa L. to predict possible ecological niches and radiation processes of hybridogenic offspring. A quantitative analysis of mechanical properties indicates that neither an expected parentally skewed nor an intermediate habit was expressed by the hybrids, but a dominant L-type as in R. canina, regardless of the parental relationship (pollen-parent or seed-parent). Our results implicate two possible scenarios to be further tested: (a) R. canina acts as a species with a dominant allele for the growth form character. If so, this would be the first evidence of a Mendelian character inheritance in the dogroses. (b) ‘Growth form’ in the dogroses is not a Mendelian character, but a syndrom which realises as an emergent functional property with underlying phenotypic structural differences in stem and wood anatomy.

Forensic genetics

Forensic genetics

CHARACTERIZATION OF A HYBRID ZONE BETWEEN CHROMOSOMALLY DIVERGENT POPULATIONS OF CTENOMYS MINUTUS (RODENTIA: CTENOMYIDAE)

This paper describes a stable chromosomal polymorphism in a species of tuco-tuco (Ctenomys minutus) and examines the dynamics of a narrow hybrid zone between chromosomal races distributed parapatrically on the coastal plain of southeastern Brazil. A cytogenetic survey studied 132 specimens of C. minutus from 22 trapping sites within the contact zone and surrounding areas. Seven polymorphic sites were identified; at all other sites, 2n was fixed for 2n = 46 or 48. A single chromosomal rearrangement is involved in the observed variation, which served as a diallelic Mendelian character in a Hardy–Weinberg analysis. Pooling polymorphic populations revealed that the mating system is random among genotypes (i.e., no mating bias is present or there is no purifying selection). Observed frequency of the metacentric chromosome follows a clinal variation. The hybrid zone is located along an ecotone, which could imply that exogenous selection is important in its maintenance. However, applying static-cline methodologies revealed weak exogenous selection, and it is possible that the hybrid zone could be the result of a relatively recent secondary contact with a width determined primarily by neutral diffusion. A historical scenario for the time, place or origin, and spread of the species and its chromosomal races is also presented.

Adhesion of K88ab fimbriated E. coli in piglet small intestines in relation with iron transport molecules.

Enteropathogenic K88 fimbricated E. coli colonize the piglet small intestine. In swine, it has been previously established that some pigs lack intestinal receptors for K88 lectins and that these animals are resistant to infections by K88-positive E. coli. The receptor is inherited as a simple mendelian character. The interactions established between the glycoconjugate receptors of pig brush borders and K88 lectins are mediated by O- and N-linked glycoproteins which differ between adhesive and non-adhesive piglets. In this study the adhesion of E. coli K88+ in crossbred F2 (LW x MS) x (LW x MS) populations. By using in vitro brush border test, we observed modulation of the adhesion of K88 fimbriae and distinguished high and low affinity receptors. Furthermore, we correlated the attachment with glycoprotein pattern of epithelial cells and mucus. Epithelial cells and mucus contained several glycopeptides (from 42 to 74 kDa) recognized by K88ab fimbriae. The 74 kDa glycoprotein was characteristic of adhesive phenotype and was a mucosal transferrin (iTf). It appeared that iTf was more abundant in adhesive intestines than in non-adhesive ones, suggesting that susceptibility/resistance phenotype could be related to iron metabolism in the intestinal tract. Furthermore, we visualized the intestinal transferrin receptors on the brush border membrane of epithelial cells, probably implicated in iron absorption.

Tempo and mode in evolution.

George Gaylord Simpson said in his classic Tempo and Mode in Evolution (1) that paleontologists enjoy special advantages over geneticists on two topics. One general topic, suggested by word tempo, has to do with evolutionary rates. . ., their acceleration and deceleration, conditions of exceptionally slow or rapid evolutions, and phenomena suggestive of inertia and momentum. A group of related problems, implied by word mode, involves the study of way, manner, or pattern of evolution, a study in which is a basic factor, but which embraces considerably more than tempo (pp. xvii-xviii). Simpson's book was self-consciously written in wake of Theodosius Dobzhansky's Genetics and Origin of Species (2). The title of Dobzhansky's book suggested its theme: role of genetics in explaining the origin of species-i.e., a synthesis of Darwin's theory of evolution by natural selection and maturing science of genetics. In introduction to his book, Simpson averred that an essential part of his study was an attempted synthesis of paleontology and genetics, an effort that pervaded whole book, but was particularly subject of first two chapters, which accounted for nearly half book's pages. Darwin believed that change occurs by natural selection of small individual differences appearing every generation within any species. Singly changes effected by selection are small but, given enough time, great changes can take place. Two of Darwin's most dedicated supporters, Thomas Huxley and Francis Galton, argued instead that evolution occurs by selection of discontinuous variations, or sports; evolution proceeds rapidly by discrete leaps. According to Huxley, if natural selection operates only upon gradual differences among individuals, gaps between existing species and in paleontological record could not be explained. For Galton, evolution was not a smooth and uniform process, but proceeded by jerks, some of which imply considerable organic change. This controversy was continued in latter part of nineteenth century by biometricians Karl Pearson and W. F. R. Weldon, who believed, like Darwin, in primary importance of common individual differences, and by geneticist William Bateson, who maintained primary importance of discontinuous variations. The rediscovery of Mendelian inheritance in 1900 provided what might have been common grounds to resolve conflict. Instead, dispute between biometricians and geneticists extended to continental Europe and to United States. Bateson was champion of Mendelians, many of whom accepted mutation theory proposed by De Vries, and denied that natural selection played a major role in evolution. The biometricians for their part argued that Mendelian characters were sports of little importance to process.

Conflicts in human progress: sexual selection and the Fisherian ‘runaway’

R. A. Fisher is perhaps best known for his influential theoretical contributions to the ‘Evolutionary Synthesis’ of the 1930s and 1940s in which biometry was reconciled with Mendelism. It is no accident, I believe, that when historians discuss the ‘Synthesis’, the names R. A. Fisher, Sewall Wright and J. B. S. Haldane are nearly always given in that order. Fisher's 1918 paper ‘The correlation between relatives on the supposition of Mendelian inheritance’ suggested that biometry, which emphasized the distribution of characters based on continuous variation, and Mendelism, which emphasized discontinuous characters, were compatible and could be united to study evolutionary change. If one considered large numbers of discontinuous, Mendelian characters, then statistical biometrical analysis could be conducted. Thus, Fisher argued, biometry and Mendelism need not oppose each other.

President's Address: Twins and Genetic Studies of Man

The International Society for Twin Studies is a unique organization. It is unique in the status of members composing the Society. In addition to specialists of science and medicine we have non-specialist members including twins and their families, all enjoying excellent collaboration in undertaking research and related activities of common interest. This kind of collaboration is very important for academic societies, particularly for those devoting themselves to the studies of man. We aim at a better understanding of man; our purpose is to learn more about ourselves. This activity is not a monopoly of specialists. Our achievements should also be shared by lay people. ISTS can serve as a model for academic societies aiming at the studies of man. Science has the solid ground of logos. At the same time, we realize that the accomplishments of highly specialized science should be reevaluated in the light of human values. I am inclined to believe that our task is to integrate the logos of scientists and ethos of the public into one.The purpose of twin studies is two-fold; studying multiple birth phenomena per se, and making inquiry into the genetic and environmental sources of human variation. The latter task was initiated by a number of pioneers in the early twentieth century. At that time, however, genetic studies of man including twin studies remained largely descriptive. We could not, and still cannot, perform genetic experiments on human individuals and populations, and the methodology available was limited to observation of a character presented in pedigree members and twins. However, despite the limitation of methodology, classical pedigree analysis has permitted us to accumulate a large amount of data on normal hereditary traits and genetic diseases, or more precisely, simple Mendelian characters.

Biochemical genetics and fishery management: an historical perspective

This paper traces the development of applications of biochemical genetic methods to problems of fishery management over a period of four decades. In the 1950s, details of presumed genetic structuring offish species appeared destined for revelation through Mendelian characters identified by immunogenetic procedures. In the 1960s, immunogenetic methods were displaced by protein electrophoresis, with a proliferation of reports of genotypic and allelic data for protein‐coding loci. In the 1970s, disagreement about the biological significance of protein polymorphisms delayed acceptance of management applications of this variation. In the 1980s, management applications included identification of relationships among populations, analyses of mixed stock fisheries, and uses in fish culture, conservation biology and forensics. The complementary relationship between protein electrophoresis and nucleic acid technologies is stressed, with a plea to recognize the unique attributes of properly applied protein electrophoresis in fishery management.

Characterization of a Schizosaccharomyces pombe morphological mutant altered in the galactomannan content

In a search for Schizosaccharomyces pombe mutants resistant to the antifungal agent papulacandin B, a morphological mutant was isolated. The mutant is round shaped in contrast to the rod shaped parental strain. This morphological defect segregated as a recessive Mendelian character and was not observed in other papulacandin B resistant mutants belonging to the same complementation group. The mutation mapped in the right arm of S. pombe chromosome III very close to pap1 marker. Mutant cell walls were more susceptible to alkali extraction and Novozyme degradation than those from the wild-type. A specific reduction in the cell wall galactomannan fraction was the only significant difference detected as compared to the wild-type strain. Levels of beta (1,3)-glucan and mannan synthases as well as other enzymic periplasmic mannoproteins were very similar in wild type and mutant strains.

Genetic analysis of the wing‐form determination of the small brown planthopper, Laodelphax striatellus (Hemiptera: Delphacidae)

SummaryThe mechanism of the genetic control of wing form determination of the small brown planthopper Laodelphax striatellus was analyzed by selection and crossing experiments. The selection experiment for brachypterous and macropterous forms for 13 generations showed that the wing form is under some genetic control. The crossing experiment showed that the wing form polymorphism was not a simple Mendelian character but was under polygenic control. The data from the crossing experiment were applied to the liability method for the quantitative genetics by Falconer (1981). The analysis suggested that wing form determination was a threshold character under polygenic control, and the estimated minimum number of loci concerned was 2.07. The realized heritability estimated from the data of selection experiment was 0.36 for macroptery. On the other hand, the heritability in broad sense estimated on the basis of the variance of F1 and F2 in crossing experiment was 0.81.