Estimation of male to female ratio of mutation rates from carrier-detection tests in X-linked disorders.

A method is presented for the estimation of the ratio of male to female mutation rates from female carrier-detection test data from pedigrees containing an isolated male manifesting an X-linked necessive disorder. Pedigrees of any size and complexity (barring consanguinity) and containing any number of tested females can be utilized. The relative fitness of affected males and carrier females, and the segregation probability of the abnormal gamete in females, can be estimated simultaneously with the ratio of mutation rates in order to test specific hypotheses against given bodies of data. Here this method is applied to families containing isolated individuals affected with Lesch-Nyhan syndrome.     

Predictive diagnosis of familial adenomatous polyposis with linked DNA markers: population based study.

OBJECTIVES--To evaluate the use of polymorphic DNA probes linked to the APC gene in the presymptomatic diagnosis of familial adenomatous polyposis. DESIGN--Four DNA probes were tested on an unselected population of patients at risk of familial adenomatous polyposis. SUBJECTS--The first 47 families notified to the West Midlands familial adenomatous polyposis register. Plus five families sent to our hospital as part of the West of Britain DNA consortium. MAIN OUTCOME MEASURES--The proportion of families and family members in whom DNA testing could be used to adjust the estimate of risk. RESULTS--Only 17 families on the register (containing 46% (74/162) of the population at risk) had a suitable pedigree structure for DNA analysis. DNA was analysed in 12 of these families plus the five families from the West of Britain consortium. At least one probe was informative in 27 of the 33 subjects born with 50% risk, but the most informative probe (pi 227) was the one with the highest recombination rate (10%). Flanking markers were informative in only four of the 33 subjects. CONCLUSIONS--These findings confirm the potential for accurate predictive diagnosis of familial adenomatous polyposis with polymorphic DNA probes, but such an approach is currently limited to about one third of affected families. A combined approach to presymptomatic diagnosis, which includes DNA testing and indirect ophthalmoscopy, is advocated.     

Human sex ratios and sex distribution in sibships of size 2

We previously analyzed data from the U.S. National Health Interview Survey (NHIS, 1998 to 2002) on families with two biological children (10 years of age and younger) and found that the distribution of families with two boys, two girls, and one boy + one girl did not statistically conform to a binomial distribution regardless of the boy/girl sex ratio used. Using the best estimate of the sex ratio from the data, we found that there were significantly more families with opposite-sex siblings than families with same-sex siblings. No biological mechanism could explain these results at the time. In the present study we conducted an analysis of the first two children in sibships of size 3 from the same data source and found that there are significantly more same-sex sibships than unlike-sex sibships. Combining the two sets of data for the first two children produced observed numbers in close agreement with the expected numbers. A hypothesis of parental choice (family planning) appears to be strongly supported as an explanation for the discrepancies in the two sets of data individually. For example, parents who have a boy and a girl (either order) as their first two children are more likely to stop having children ("stopping rule") than are parents whose first two children are of the same sex.     

The effects of sex preselection on the sex ratio of families

Advances in the potential for couples to predetermine the sex of their children will have significant consequences for many aspects of society. Among the likely demographic impacts are changes in both population size and the sex ratio. The aim of this article is to assess the effects of sex preselection on the sex ratio of families. The expected family sex ratio is derived and characterized for couples with particular preferences for the sex composition of their families. When couples desire k children of one sex and none of the other, the proportion of children in the completed family that are of the desired sex falls with increasing k. Constraints on total family size further reduce this proportion. When couples have a desire for a balanced composition of one boy and one girl, and when they have a preference for, say, a boy to be born first, they can expect a proportion of boys in the family that at first rises, and then falls, as sex preselection methods improve.     

Familial high myopia: evidence of an autosomal dominant mode of inheritance and genetic heterogeneity.

High myopia, defined as a refractive error inferior to -6 diopters, often appears as a familial disease. In order to precise its genetic background, we performed a segregation analysis on 32 French families (320 subjects including 120 individuals with clinical data) containing at least one high myopic person in their genealogy. Under the assumption of a two-alleles single gene model, the autosomal dominant transmission mode showed a much greater likelihood than the autosomal recessive mode, which therefore was rejected. From the segregation model obtained, a two-point linkage analysis was made on 18 families (107 subjects), among the 32 used for the segregation analysis. Different candidate loci were tested: collagen genes including Stickler syndrome types 1 and 2, proteoglycan genes, Marfan 1 syndrome and a Marfan like disorder localised in 3p24.2-p25. No evidence of linkage was found with any of the studied markers. In addition, the absence of linkage with chromosome 18p11.31 markers, a locus linked to familial high myopia in 6 North American families and 1 family of Chinese descent, demonstrated the genetic heterogeneity of the disease.     

On the virtue of being the first born: the influence of date of birth on fitness in the mosquitofish, Gambusia affinis

We found in an earlier study that mosquitofish (Gambusia affinis and G. holbrooki) ceased reproduction in the late summer, long before the end of warm weather, stored fat, then utilized reserves to survive the winter and initiate reproduction the following spring. We hypothesized that this pattern of fat utilization was a life history adaptation that enabled the fish to acquire food resources in the autumn then allocate them to reproduction the following spring when the fitness of the young would be greater. Here we evaluate one aspect of this hypothesis by evaluating the probability of survival to maturity and fecundity of young as a function of date of birth. We placed cohorts comprising eight to ten litters of young born early‐, mid‐ or late in the reproductive season in replicate field enclosures. The entire experiment was repeated in two different years. Early‐born young had a significantly higher probability of survival to maturity but did not differ in fecundity relative to the last cohort of the season. Early‐born young also attained maturity early enough to reproduce in their year of birth while late‐born young had to overwinter before reproduction. The fitness consequences to the mother of either producing one more litter of young at the end of the season, versus instead storing fat and reproducing the following spring are not as determinate as are the effects of date of birth on offspring fitness. Females most often gain fitness by not producing one last litter and instead over‐wintering. If, however, the overwinter survival of offspring is not influenced by their size at the end of the season, then a female's fitness could be enhanced by producing one more litter late in the season. If instead the probability of overwinter survival is strongly influenced by the size of offspring at the end of the season, then our results suggest that a female gains more by deferring reproduction and storing for overwinter survival and reproduction the following spring.     

An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome

The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.     

Correlation of intergenerational family sizes suggests a genetic component of reproductive fitness

Reproductive fitness is a complex phenotype that is a direct measure of Darwinian selection. Estimation of the genetic contribution to this phenotype in human populations is confounded by within-family correlations of sociocultural, economic, and other nongenetic factors that influence family sizes. Here, we report an intergenerational correlation in reproductive success in the Hutterites, a human population that is relatively homogeneous with respect to sociocultural factors that influence fertility. We introduce an estimator of this correlation that takes into account the presence of multiple parent-offspring pairs from the same nuclear family. Statistical significance of the estimated correlation is assessed by a permutation test that maintains the overall structure of the pedigree. Further, temporal trends in fertility within this population are accounted for. Applying these methods to the S-Leut Hutterites yields a correlation in effective family size of 0.29 between couples and their sons and 0.18 between couples and their daughters, with empirical P<1x10-6 and P=.0041, respectively. Similar results were obtained for completed families (0.31 between couples and their sons and 0.23 between couples and their daughters; empirical P<1x10-6 and P=.00059, respectively). We interpret these results as indicating a significant genetic component to reproductive fitness in the Hutterites.     

Family-size distribution and Ewens'' equivalence theorem.

Segregation analysis of a data set containing nuclear families of more than one sibship size is considered, and two different formulations of the likelihood are examined. One is the "separate-multinomials" formulation, which treats each family size as representing a separate multinomial distribution; the other is the "grand-multinomial" formulation, which treats the entire data set as representing one distribution. It is shown that these two formulations are equivalent, if and only if the population distribution of family sizes is completely unknown. However, if anything is known about the family-size distribution, the grand-multinomial formulation, although more cumbersome, makes more complete use of the data; moreover, it enables the use of one-child families in a segregation analysis. The relationship of this work to Ewens' equivalence theorem concerning "unconditional" and "conditional" likelihoods is discussed. The findings are illustrated with a simple example, and their practical relevance to real-life segregation analysis is discussed.     

Family dynamics and age-related patterns in marriage probability

In cooperatively breeding species, extended living in natal families after maturity is often associated with limited breeding possibilities and the ability to gain indirect fitness from helping relatives, with family dynamics, such as parental presence and relatedness between family members, playing a key role in determining the timing of own reproduction. How family dynamics affect marriage and the onset of reproduction in humans is complex and less well-understood. While paternal absence can be associated with both earlier puberty and reproductive behaviour, or with delayed reproduction if marriage requires parental resources, in step-parent families, half-siblings could further decrease the benefits from helping and delaying own reproduction compared to families with only full-siblings. Such costs and benefits are likely age-dependent, but have not been addressed in previous studies. Using data from pre-industrial agrarian Finland, we investigated if parental loss and remarriage affected marriage probabilities of their differently-aged sons and daughters. We found that parental composition had divergent effects across adulthood: loss of a parent resulted in a higher probability to marry in early adulthood, whereas parental presence increased later adulthood marriage probability. Whilst the death of either parent was linked to an overall lowered marriage probability, remarriage of the widowed parent, especially mother, could mitigate this effect somewhat. Additionally, the presence of underage full-siblings lowered marriage probability, suggesting postponement of one's own reproduction in favour of helping parental reproduction. Overall, our results support the idea that humans are cooperative breeders, and show the importance of considering both relatedness and age when investigating family dynamics.     

被子植物非国产科汉名的初步拟订

报道了中国产12种苔藓植物染色体数目,结果为:壶苞苔Blasia pusilla,n=9;艳 绿光苔Cyathodium smaragdinum,n=9;紫背苔Plagiochasma rupestre,n=9;石地钱Rebou lia hemisphaerica,n=9;宽片叶苔Riccardia latifrons,n=10;尖叶美喙藓Eurhynchium eustegium,n=11;东亚沼羽藓Helodium sachalinense,n=11;白齿藓Leucodon sciuroides,     

Possible Balancing Selection in Human Female Homosexuality

A growing number of researchers suggest that female homosexuality is at least in part influenced by genetic factors. Unlike for male homosexuality, few familial studies have attempted to explore maintenance of this apparently fitness-detrimental trait in the population. Using multiple recruitment methods, we explored fecundity and sexual orientation within the pedigrees of 1,458 adult female respondents. We compared 487 homosexual and 163 bisexual with 808 heterosexual females and 30,203 of their relatives. Our data suggest that the direct fitness of homosexual females is four times lower than the direct fitness of heterosexual females of corresponding ages. The prevalence of nonheterosexuality within the homosexual female respondents’ families (2.83%) appear to be more than four times higher than the basal prevalence in the Italian population (0.63%). Pedigree size and relative fecundity in both the paternal and maternal sides of the homosexual women’s families were significantly higher than in the heterosexuals’ families. If confirmed, the relative average fecundity increase within the family seems to offset the loss in fitness due to the low direct fitness of homosexual females. Therefore, the balanced fecundity in the homosexual females’ families may allow the trait to be maintained at a low-frequency equilibrium in the population.     

Familiärer Darmkrebs

Up to 5% of colorectal cancer cases are caused by a monogenic inherited disposition. Among these, hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) accounts for 2–3% and adenomatous polyposis syndromes (familial adenomatous polyposis, FAP and MUTYH-associated polyposis, MAP) for about 1% of cases. Hamartomatous polyposis syndromes (juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome) are rare disorders that are also associated with an increased colorectal cancer risk. The genetic basis is largely known for the tumour syndromes mentioned above. The identification of the causative germline mutation in the respective DNA repair genes (e.g. in HNPCC and MAP) or tumour suppressor genes (FAP or hamartomatous polyposis syndromes) allows confirmation of the diagnosis in affected individuals and provides predictive diagnostics for their healthy relatives. To achieve a targeted and useful molecular diagnostics, it is important that the clinician provides a detailed characterisation of the clinical picture; moreover, family history may also give a hint of the underlying gene defect. The screening of tumour tissue for the presence of a mismatch repair defect should precede mutation analysis in suspected cases of HNPCC, as it is difficult to differentiate between this condition and sporadic colorectal cancer. In contrast, mutation analysis can be directly performed in polyposis syndromes provided the syndrome has been correctly classified by the histology of polyps.     

Linkage Analysis in Familial Non-Lynch Syndrome Colorectal Cancer Families from Sweden

Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.     

Expected gain and status number following restricted individual and combined-index selection.

Imposition of restrictions on number of individuals selected from a family and number of families from which superior individuals are selected could markedly alter the consequences of individual and combined-index selection. Predicted genetic gain and diversity measured as status number following selection were studied to draw general conclusions. Selection and its prediction were applied to two sets of real-life data. Theoretical prediction gave results close to those from factual selection. Gain and status number varied with initial family number and size, sib type, heritability, selection proportion, restriction type and intensity, and selection criteria. Proper restriction on the number of individuals selected can control the reduction of status number to an acceptable level, particularly when breeding values are used as the selection criterion. Restriction on the number of families selected would effectively improve the gain efficiency of selection based on phenotypic values. Choosing combinations of both restrictions might produce higher gain without the loss of status number. Given constant population size, family number should be large enough to ensure that restricted selection will yield higher gain and status number.     

The Dyggve-Melchior-Clausen syndrome.

Two new cases of Dyggve-Melchior-Clausen syndrome are described; they belong to the fourth family from Lebanon in which this disease has been recognized. There is no genealogical linkage between these four families. A particular feature in these cases is a striking rhizomelic shortness of the arms especially in one case. Clinical and radiological findings, progression of the skeletal changes are studied, along with the review of the cases in the literature. Cytological and biochemical data indicate that the DMC syndrome is not a mucopolysaccharidosis.     

Referent sampling,family history and relative risk: the role of length-biased sampling

Familial risk of disease is often assessed using case control studies based on referent databases. A referent database is a collection of family histories of cases typically assembled as a result of one family member being diagnosed with disease. This sampling scheme is equivalent to sampling families proportional to their size. The larger the family, the greater the probability of finding the family in the referent registry. This phenomena is known as length-biased sampling. The consequence of this kind of sampling is to bias the regression estimate associated with family history. The estimate is typically inflated in comparison to what is true for the actual population.     

Novel germline mutations in the APC gene and their phenotypic spectrum in familial adenomatous polyposis kindreds

Among 23 germline mutations identified in the APC screening of 45 familial adenomatous polyposis (FAP) patients, we have found 10 different novel frameshift mutations in 11 apparently unrelated patients. In two cases, an additional missense mutation was detected. One previously described as a causative germline mutation (S2621C), associated with a 1-bp insertion (4684insA) on the opposite allele, did not segregate with the FAP phenotype in the family and was therefore considered as being non-pathogenic. The other (Z1625H) was located 2 codons before a 1-bp deletion (4897delC). Both mutations were transmitted together from an FAP father to his affected son. The FAP phenotype of these 10 novel truncating mutations was clinically documented within their kindreds. Important variability was observed in the phenotype. Interestingly, we noted that a mutation (487insT) localized at the boundary of the 5’ attenuated APC phenotype region in two unrelated families resulted in classical polyposis. A clear-cut genotype-phenotype correlation could be drawn in only two instances. In one family, a 4684insA mutation led to a mild polyposis associated with early inherited osteomas and, in the family bearing the double mutation (Z1625H+4897delC), the phenotype was obviously a 3′ attenuated type. Our data illustrate the wide genetic and phenotypic heterogeneity of this condition between and within the families, making the establishment of correlations complex and any prediction in this disease difficult, although targeting the mutation site may be helpful in some specific cases. Received: 11 February 1997 / Accepted: 11 April 1997