Unusual clustering of diseases in a Canadian Old Colony (Chortitza) Mennonite kindred and community.

We investigated a large Old Colony (Chortitza) Mennonite kindred with branches across Canada. Six generations of the kindred were traced. There was intermarriage among numerous family members. Insulin-dependent diabetes mellitus (IDDM) was identified in 10 members; all 7 living patients were found to carry the immunogenetic marker HLA-DR4. Nine other close relatives had disorders of carbohydrate metabolism, including gestational diabetes mellitus and non-insulin-dependent diabetes mellitus progressing to insulin use. Ten other relatives had autoimmune diseases, including rheumatoid arthritis, hyperthyroidism, hypothyroidism and multiple sclerosis. Cases of Alport''s syndrome, congenital malformations, inborn errors of metabolism and unusual malignant diseases were also found in the kindred. In the small Alberta community in which the kindred was ascertained there were people of Old Colony Mennonite descent with genetic conditions such as Gilles de la Tourette''s syndrome and congenital malformations, including congenital heart disease. This kindred represents the largest reported familial aggregation of IDDM. This disease and other disorders of carbohydrate metabolism occur in the context of a strong familial predisposition to autoimmune disease. Study of this family may permit empiric testing of proposed models of inheritance of diseases of complex origin such as IDDM. We report this Old Colony (Chortitza) Mennonite community because it is one of the settlements populated by this religious and genetic isolate, which extends across Canada and Central and South America and affords opportunities for the study of both common and rare inherited diseases.     

Analysis of the contribution of HLA genes to genetic predisposition in inflammatory bowel disease.

Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have a 10-fold increase in risk of developing the same disease, and distinct associations between specific HLA types and both CD and UC have been reported. We have evaluated the contribution of genes at the HLA locus to susceptibility in IBD by linkage analysis of highly informative microsatellite polymorphisms in 43 families with multiple affected cases. No evidence for linkage of HLA to IBD was obtained under any of the four models tested. Analysis of HLA haplotype sharing in affected relatives indicated that the relative risk to a sibling conferred by the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits of 2.41 and 1.37, respectively. This suggests that other genetic or environmental factors are responsible for most of the familial aggregation in IBD.     

Complementation and maternal effect in insulin-dependent diabetes.

The marker association segregation chi-square (MASC) method was applied to a sample of 416 Caucasians affected with insulin-dependent diabetes mellitus (IDDM), for which information on the parental and sibship status was available, as well as HLA typing. We show that the model which best explains all the observations assumes a cis or trans complementation of two tightly linked genes within the HLA region, an additional maternal effect, and other familial factors. The HLA molecule corresponding to the complementation of Arg52(+) and Asp57(-) has been recently proposed as explaining susceptibility to IDDM. However, this hypothesis does not account for the overall observations made on the HLA marker in IDDM patients and their relatives. The MASC method may also be applied to evaluate the risk for relatives of an affected individual (the "index"). For example, the risk for a sib depends not only on the parental status and on the number of HLA haplotypes he shares with the index, but also on which haplotype the index himself inherited from his mother and father.     

Hereditary site-specific colon cancer in a Canadian kindred.

A large kindred with colorectal cancer unaccompanied by polyposis coli and characterized by autosomal dominant inheritance has been identified in eastern Canada. Ten family members from three successive generations have presented 17 documented colorectal cancers. The clinical features of the kindred are characteristic of hereditary site-specific colon cancer (HSSCC) (Lynch syndrome I): absence of multiple polyposis, autosomal dominant inheritance, onset of colorectal cancer at an early age and a high incidence of synchronous and metachronous colorectal cancers. A unique feature of this family is the high incidence of sporadic adenomatous polyps in affected members and their relatives. Patients with HSSCC have been managed by means of segmental colectomy followed by annual colonoscopic surveillance. All five patients with localized (Dukes'' stage A or B) cancer at initial diagnosis were alive and free of disease after 2 to 12 years of follow-up, although three had required further colonic resection for metachronous carcinomas. Five young family members without cancer have had sporadic adenomatous polyps removed and are being followed with annual colonoscopy. It is not known whether polypectomy will alter the subsequent incidence of colon cancer. Subtotal colectomy is recommended for patients with HSSCC because of the high incidence of multiple lesions. An aggressive screening protocol, including colonoscopy, is recommended for all adult first- and second-degree relatives of patients with HSSCC. Identification of a biomarker, which is currently being sought in this kindred, would help identify those at greatest risk of development of cancer and allow earlier intervention.     

Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease.

BACKGROUND: Individuals at risk for insulin-dependent diabetes mellitus (IDDM), with an affected first-degree relative, can be identified by the presence of islet cell antibodies (ICA). ICA-positive relatives progress at variable rates to IDDM and identification of those at highest risk is a prerequisite for possible preventative treatment. Those who develop IDDM may exhibit less genetic heterogeneity than their ICA-positive or ICA-negative relatives. Specific human leucocyte antigen (HLA) genes predispose to IDDM but could also influence the rate of progression of preclinical disease. Therefore, by comparing HLA antigen frequencies between first-degree relatives, we sought to identify HLA genes that influence progression to IDDM. MATERIALS AND METHODS: HLA antigen frequencies were compared in 68 IDDM, 53 ICA-positive, and 96 ICA-negative first-degree relatives from 40 Caucasoid families. Predictions were tested in a panel of 270 unrelated IDDM subjects. HLA typing was performed serologically (HLA class I and II) and by sequence-specific oligotyping (11th International Histocompatibility Workshop protocol) (HLA class II). ICA tests were measured by an internationally standardized indirect immunofluorescence assay. RESULTS: In general, known susceptibility class II HLA antigens increased in frequency and known protective class II HLA antigens decreased in frequency, from ICA-negative to ICA-positive to IDDM relatives. Thus, DR4 and DQ8 increased whereas DR2 and DQ6 decreased; DR3 and DQ2 increased from ICA-negative to ICA-positive relatives, but not further in IDDM relatives. The high-risk DR3, 4 phenotype increased across the three groups; DR4,X was unchanged, and DR3,X and DRX,X both decreased. The HLA class I antigen, A24, occurred more frequently in ICA-positive relatives who developed IDDM and, in 270 unrelated IDDM subjects, was associated with an earlier age at diagnosis of IDDM in those with the lower risk class II phenotypes DR4,4 and DR3,X. CONCLUSIONS: HLA-DR3 and DQ2 predispose to islet autoimmunity, but not development of clinical IDDM in the absence and DR4 and DQ8. DR4 and DQ8 predispose to the development of clinical IDDM in ICA-positive relatives, in combination with DR3-DQ2 and other haplotypes but not when homozygous. HLA-A24 is significantly associated with rapid progression to IDDM in ICA-positive relatives and with an earlier age at clinical diagnosis. Analysis of IDDM families reveals that HLA genes not only predispose to islet autoimmunity but influence progression to clinical disease. The findings have implications for identifying high-risk relatives as candidates for possible preventative therapy.     

Increased frequency of islet cell antibodies in unaffected brothers of children with type 1 diabetes

AIM: To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D). METHODS: Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1-51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases. RESULTS: Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3-514) JDF units vs. 10 (range 3-564) JDF units; p = 0.008]. Among the adult relatives (>or=20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5-564) JDF units vs. 9 (range 3-130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (>or=18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01). CONCLUSIONS: These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (>or=18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.     

Craniofacial features associated with amelogenesis imperfecta

Craniofacial alterations occur with increased frequency in patients with amelogenesis imperfecta (AI). The purpose of this study was to characterize the craniofacial features associated with AI in families from the US. Twenty-seven people with AI and 14 unaffected family members from nine separate kindreds were evaluated. The diagnosis was established by history, clinical, and radiographic examination, and histological and or biochemical analysis of enamel. The kindreds were generally classified as hypoplastic AI (HPAI), hypocalcified AI (HCAI), or hypomaturation AI (HMAI) and then further subclassified based on phenotype and mode of inheritance. Linear and angular cephalometric measures were converted to z-scores using gender/age matched values from the Bolton and Behrent's standards. Statistical analyses included t-tests and ANOVA accepting P < or = 0.05 as significant. The vertical dimension of the lower face was significantly increased (ANSMe; P = 0.001), especially in affected individuals compared with unaffected relatives, in all kindreds with HCAI and HMAI but in only one kindred with autosomal recessive rough AI. Clinically, an anterior open bite (overbite < 0 mm) was observed in 26% of all dentate individuals with AI and none of their unaffected relatives. Skeletal morphology was highly variable depending on the AI type and kindred. While this study shows an association of altered craniofacial morphology with certain AI kindreds, the relationship of the AI genotype to the observed malocclusions remains to be defined.     

Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.

van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.     

Alzheimer disease: evidence for susceptibility loci on chromosomes 6 and 14

We report the transmission of HLA haplotypes and Gm allotypes in 97 members of a single kindred containing 257 individuals, 45 of whom were determined by clinical examination, autopsy, or historical data to have had Alzheimer disease (AD). Extensive inbreeding suggests that more than one gene may contribute to susceptibility to AD in this family, despite the apparent vertical transmission of illness. The distribution of HLA haplotypes and of Gm allotypes to affected and unaffected siblings is consistent with the possibility that genes in the HLA region of chromosome 6 and perhaps also in the Gm region of chromosome 14 are determinants of susceptibility. Further studies are needed to investigate whether susceptibility to AD may result from an interaction between (immune response?) genes on these two chromosomes.     

Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31-q33.

Familial eosinophilia (FE) is an autosomal dominant disorder characterized by peripheral hypereosinophilia of unidentifiable cause with or without other organ involvement. To localize the gene for FE, we performed a genomewide search in a large U.S. kindred, using 312 different polymorphic markers. Seventeen affected subjects, 28 unaffected bloodline relatives, and 8 spouses were genotyped. The initial linkage results from the genome scan provided evidence for linkage on chromosome 5q31-q33. Additional genotyping of genetic markers located in this specific region demonstrated significant evidence that the FE locus is situated between the chromosome 5q markers D5S642 and D5S816 (multipoint LOD score of 6.49). Notably, this region contains the cytokine gene cluster, which includes three genes-namely, those for interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF)-whose products play important roles in the development and proliferation of eosinophils. These three cytokine genes were screened for potential disease-specific mutations by resequencing of a subgroup of individuals from the present kindred. No functional sequence polymorphisms were found within the promoter, the exons, or the introns of any of these genes or within the IL-3/GM-CSF enhancer, suggesting that the primary defect in FE is not caused by a mutation in any one of these genes but, rather, is caused by another gene in the area.     

Assessing the role of HLA-linked and unlinked determinants of disease.

The relationship between increased risk in relatives over population prevalence (lambda R = KR/K) and probability of sharing zero marker alleles identical by descent (ibd) at a linked locus (such as HLA) by an affected relative pair is examined. For a model assuming a single disease-susceptibility locus or group of loci tightly linked to a marker locus, the relationship is remarkably simple and general. Namely, if phi R is the prior probability for the relative pair to share zero marker alleles identical by descent, then P (sharing 0 markers/both relatives are affected) is just phi R/lambda R. Alternatively, lambda AR, the increased risk over population prevalence to a relative R due to a disease locus tightly linked to marker locus A, equals the prior probability that the relative pair share zero A alleles ibd divided by the posterior probability that they share zero alleles ibd, given that they are both affected. For example, for affected sib pairs, P (sharing 0 markers/both sibs are affected) = .25/lambda S. This formula holds true for any number of alleles at the disease locus and for their frequencies, penetrances, and population prevalence. Similar formulas are derived for sharing one and two markers. Application of these formulas to several well-studied HLA-associated diseases yields the following results: For multiple sclerosis, insulin-dependent diabetes mellitus, and coeliac disease, a single-locus model of disease susceptibility is rejected, implying the existence of additional unlinked familial determinants. For all three diseases, the effect of the HLA-linked locus on familiality is minor: for multiple sclerosis, it accounts for only a 2.5-fold increased risk to sibs over the population prevalence, compared to an observed value of 20; for coeliac disease, it accounts for approximately a 5.25-fold increased risk to sibs, while the observed value is on the order of 60; for insulin-dependent diabetes mellitus, it accounts for a 3.42-fold increased risk in sibs, while the observed value is 15. In all cases, the secondary determinants must be outside the HLA region. For tuberculoid leprosy, an unlinked familial determinant is also implicated (increased risk to sibs due to HLA = 1.49; observed value = 2.38). For hemochromatosis and Hodgkin's disease, there is little evidence for HLA-unlinked familial determinants. With this formula, it is also possible to examine the hypothesis of pleiotropy versus linkage dis-equilibrium by comparing lambda AS with the increased risk to sibs due to the associated allele(s).(ABSTRACT TRUNCATED AT 400 WORDS)     

The use of association data to identify family members at high risk for marker-linked diseases.

The study of genetic markers linked and associated with disease has provided important evidence of a genetic contribution to numerous diseases and has helped to establish their modes of inheritance. However, this information has not been fully utilized in counseling individuals at risk for these disorders. In the case of recessive, marker-linked diseases, such as idiopathic hemochromatosis linked to HLA in family studies and associated with specific HLA alleles in population surveys, the only current clinical application has been to identify siblings who share both HLA-marker haplotypes with the affected proband. They are considered to be presymptomatically affected, and more definitive invasive investigations are considered appropriate. All other relatives, including parents, offspring, and other siblings, who share only one marker with the proband, have been counseled only that their risk is equivalent to the gene frequency of the disease allele, for example, 3%-6% for hemochromatosis. We have developed a generally applicable method to utilize population association data to derive more specific and accurate risk figures for these other relatives of patients with marker-linked and associated diseases. We have applied this method to idiopathic hemochromatosis. If the offspring of a patient with hemochromatosis lacks A3, B7, and B14, the risk to that offspring for developing hemochromatosis is less than 2%. On the other hand, if they receive HLA A3 from their unaffected parent, their risk climbs to 9%-10%; if they receive an A3-B14 haplotype, their risk increases to virtually 100%. As demonstrated by our example, the application of association data to family members already at a basal increased risk for marker-linked disease can significantly refine the disease risk estimates given to those relatives. This information can be utilized to select individuals in whom invasive diagnostic testing or preventative intervention is indicated.     

Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).     

An intervention study to increase knowledge and use of folic acid among relatives in neural tube defect-affected families in Washington, D.C

BACKGROUND: Little is known about the level of knowledge and use of folic acid among near relatives in U.S. families of a child with spina bifida. We hypothesized that relatives would be more knowledgeable than the general population and more likely to take folic acid. Further, we hypothesized that relatives would be more motivated by an intervention to increase their use of folic acid. METHODS: We conducted an intervention study among females in families attending a hospital spina bifida clinic in Washington, DC. RESULTS: The 231 subjects consisted of the affected individuals, mothers, sisters, and aunts. The average age was 34 years. At baseline, most (87.4%) reported that they had heard of folic acid; 37.6% were currently taking multivitamins with folic acid and 6.9% were taking folic acid tablets. The intervention significantly increased both knowledge (to 99%) and intake of folic acid from 41.9 to 48.5%. Folic acid intake increased significantly among African-American women and women with less education, women who were older, married, with children, and nonsmokers. CONCLUSIONS: This intervention was successful in increasing folic acid intake among female relatives in spina bifida-affected families. By the end of the study, almost all women had heard of folic acid and folic acid use had increased by 16%. Among these women at higher than expected risk for having an affected child, this rate of intake, while more than the general population, still falls short of optimum. Fortification of food with folic acid may be the only way to ensure increased folic acid intake.     

Identity coefficients and covariances between relatives in a parent-offspring inbreeding system

Summary A one-locus operator for a younger parent-offspring inbreeding system is obtained by a generation matrix method in which 14 classes of matings are defined. The eigenvalues and a set of eigenvectors for the generation matrix and, also, the general solution for the frequencies of mating classes among descendants of an original mating of genotypes ab x cd are given. The operator gives the genotypic array of descendants of a given mating an arbitrary number of generations later. Using this operator, an algorithm is developed for calculating identity coefficients between any two relatives in a possibly branching younger parent-off spring mating system. Application to obtaining covariances between relatives for a one-locus model is illustrated.Journal article (74-3-73) of the Kentucky Agricultural Experiment Station published with approval of the Director.     

Accuracy of cancer family histories: comparison of two breast cancer syndromes

Cancer risk programs rely on accurately reported family history information. This study compares the accuracy with which cancer sites and ages at diagnosis are reported by Li-Fraumeni syndrome (LFS) and hereditary breast-ovarian cancer syndrome (HBOCS) families undergoing genetic testing. We analyzed the accuracy of 191 cancer diagnoses among first-degree (FDRs) and second-degree (SDRs) relatives reported by 32 LFS and 52 HBOCS participants in genetic testing programs. Cancer diagnoses of relatives were more accurately reported in the HBOCS cohort (78%) than in the LFS cohort (52%). Almost all breast cancer diagnoses were accurately reported, whereas 74% of ovarian cancer diagnoses and only 55% of other LFS-related cancers were accurately reported. Age at diagnosis was accurate within 5 years for 60% of LFS relatives and 53% of HBOCS relatives. Factors correlating with accurate reporting of cancer history included: being member of BRCA1 family, higher education level, female historian, degree of closeness to affected relative, and having fewer than 5 affected FDRs and SDRs. Relying on verbal histories would not have altered eligibility for genetic testing among HBOCS historians, but fewer than half of LFS historians provided information that would have led to TP53 testing. Our data suggest that it may not be necessary to confirm breast cancer diagnoses routinely; however, documentation of other cancer types remains important for appropriate risk assessment and follow-up.     

Genetic control of lecithin-cholesterol acyltransferase (LCAT): measurement of LCAT mass in a large kindred with LCAT deficiency.

Lecithin-cholesterol acyltransferase (LCAT) mass was measured by radioimmunoassay in a large Sardinian kindred with LCAT deficiency. The frequency distribution of LCAT levels in the M-kindred demonstrated a trimodal distribution, one more corresponding to the normal controls and containing the normal relatives, a second mode completely separate from the controls and containing subjects with LCAT levels approximately one-half normal, and a third mode distinct from the other modes containing the two subjects with LCAT deficiency. Fifteen kindred members, including all six spouses, had enzyme levels of 4.92 +/- 0.49 microgram/ml (mean +/- SD), slightly lower but in the same range as controls (6.13 +/- 0.98; no. = 66). Twelve family members, including the two obligate heterozygotes, had enzyme levels of 2.68 +/- 0.32 microgram/ml, roughly one-half that of control levels. The LCAT-deficient subjects had enzyme levels of 0.30 and 0.37 microgram/ml, respectively. Segregation of the acyltransferase deficiency gene (LCATd) provided clear evidence of an autosomal recessive mode of inheritance of LCAT deficiency. Furthermore, the data strongly suggest that family members with half-normal enzyme levels are heterozygous carriers of the LCATd gene.     

Microcephaly in familial holoprosencephaly

The holoprosencephaly sequence (HS) is characterized by abnormalities in forebrain cleavage and midface development. Familial holoprosencephaly has been reported in several families and there appears to be variable expression of the disorder in those who inherit the gene. Previous investigators have suggested hypotelorism and/or missing central incisors as mild manifestations of autosomal dominant HS. We evaluated a large kindred with three individuals with severe brain anomalies and 12 individuals with minor manifestations of the disorder. The most consistent sign in those mildly affected was microcephaly. We suggest that head circumference is an important part of the evaluation of the relatives of a patient with holoprosencephaly.     

A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity

We conducted a genomewide screen for prostate cancer-susceptibility genes on the basis of data from 98 families from the United States and Canada that had three or more verified diagnoses of prostate cancer among first- and second-degree relatives. We found a statistically significant excess of markers for which affected relatives exhibited modest amounts of excess allele-sharing; however, no single chromosomal region contained markers with excess allele-sharing of sufficient magnitude to indicate unequivocal evidence of linkage. Positive linkage signals of nominal statistical significance were found in two regions (5p-q and 12p) that have been identified as weakly positive in other data sets and in region 19p, which has not been identified previously. All these signals were considerably stronger for analyses restricted to families with mean age at onset below the median than for analyses of families with mean age at onset above the median. The data provided little support for any of the putative prostate cancer-susceptibility genes identified in other linkage studies.     

Moderate inbreeding depression in a reintroduced population of North Island robins

Reintroductions of threatened species are increasingly common in conservation. The translocation of a small subset of individuals from a genetically diverse source population could potentially lead to substantial inbreeding depression due to the high genetic load of the parent population. We analysed 12 years of data from the reintroduced population of North Island robins Petroica longipes on Tiritiri Matangi Island, New Zealand, to determine the frequency of inbreeding and magnitude of inbreeding depression. The initial breeding population consisted of 12 females and 21 males, which came from a large mainland population of robins. The frequency of mating between relatives ( f >0; 39%, n =82 pairs) and close relatives ( f =0.25; 6.1%) and the average level of inbreeding ( f =0.027) were within the range reported for other small island populations of birds. The average level of inbreeding fluctuated from year to year depending on the frequency of close inbreeding (e.g. sib–sib pairs). We found evidence for inbreeding depression in juvenile survival, with survival probability estimated to decline from 31% among non-inbred birds ( f =0) to 11% in highly inbred juveniles ( f =0.25). The estimated number of lethal equivalents based on this relationship (4.14) was moderate compared with values reported for other island populations of passerines. Given that significant loss of fitness was only evident in highly inbred individuals, and such individuals were relatively rare once the population expanded above 30 pairs, we conclude that inbreeding depression should have little influence on this robin population. Although the future fitness consequences of any loss of genetic variation due to inbreeding are uncertain, the immediate impact of inbreeding depression is likely to be low in any reintroduced population that expands relatively quickly after establishment.