Paternal Inheritance Research Articles

A Mouse Model for Osseous Heteroplasia

GNAS/Gnas encodes Gsα that is mainly biallelically expressed but shows imprinted expression in some tissues. In Albright Hereditary Osteodystrophy (AHO) heterozygous loss of function mutations of GNAS can result in ectopic ossification that tends to be superficial and attributable to haploinsufficiency of biallelically expressed Gsα. Oed-Sml is a point missense mutation in exon 6 of the orthologous mouse locus Gnas. We report here both the late onset ossification and occurrence of benign cutaneous fibroepithelial polyps in Oed-Sml. These phenotypes are seen on both maternal and paternal inheritance of the mutant allele and are therefore due to an effect on biallelically expressed Gsα. The ossification is confined to subcutaneous tissues and so resembles the ossification observed with AHO. Our mouse model is the first with both subcutaneous ossification and fibroepithelial polyps related to Gsα deficiency. It is also the first mouse model described with a clinically relevant phenotype associated with a point mutation in Gsα and may be useful in investigations of the mechanisms of heterotopic bone formation. Together with earlier results, our findings indicate that Gsα signalling pathways play a vital role in repressing ectopic bone formation.

A Cross‐Sectional Study on Cerebrospinal Fluid Biomarker Levels in Cognitively Normal Elderly Subjects With or Without a Family History of Alzheimer's Disease

Cerebrospinal fluid (CSF) biomarkers reflect changes in the brain, and contribute to early screening. Maternal inheritance is putatively stronger than paternal inheritance for late-onset Alzheimer's disease (LOAD). Clinical data of 162 cognitively normal subjects were reviewed. A standard questionnaire was used to identify LOAD family history. Mini-mental state examination (MMSE) was used to evaluate cognition. CSF Aβ1-40, Aβ1-42, total and phosphorylated tau were measured using ELISA. To compare biomarkers in cognitively normal elderly subjects with versus without LOAD family history. Among the 162 subjects, 38 and 60 had LOAD family history on paternal and maternal sides, respectively. The remaining 60 subjects had no family history. No difference was noted in age, gender, education level, MMSE score, and memory impairment complaint in the three groups. Aβ42 and the Aβ42/40 ratio were lower than in subjects with a maternal history than in subjects with a paternal history or without family history (P < 0.05 in both). Phosphorylated and total tau did not differ among the three groups. Offspring with a family history of LOAD on the maternal side have lower Aβ42 and Aβ42/40 ratio in the CSF, and maybe at higher risk for developing AD.

Non-random mating, parent-of-origin, and maternal–fetal incompatibility effects in schizophrenia

Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case–control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal–fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal–fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting.

Nongenetic inheritance and the evolution of costly female preference

In species where males provide neither direct benefits nor paternal care, it is typically assumed that female preferences are maintained by indirect selection reflecting genetic benefits to offspring of preferred males. However, it remains unclear whether populations harbour sufficient genetic variation in fitness to support costly female preferences - a problem called the 'lek paradox'. Here, we ask whether indirect selection on female preferences can be maintained by nongenetic inheritance. We construct a general model that can be used to represent either genetic or nongenetic inheritance, depending on the choice of parameter values. Interestingly, we find that costly preference is most likely to evolve and persist when fitness depends on an environmentally induced factor that can be transmitted over a single generation only, such as an environment-dependent paternal effect. Costly preference can also be supported when fitness depends on a highly mutable factor that can persist over multiple generations, such as an epigenetic mark, but the necessary conditions are more restrictive. Our findings show that nongenetic inheritance provides a plausible hypothesis for the maintenance of costly female preferences in species where males provide no direct benefits to females. Nongenetic paternal inheritance of fitness can occur in species lacking conventional forms of paternal care. Indeed, transmission of paternal condition via sperm-borne nongenetic factors may be more likely to evolve than conventional forms of paternal investment because sperm-borne effects are protected from cuckoldry. Our results furnish a novel example of an interaction between genetic and nongenetic inheritance that can lead to otherwise unexpected evolutionary outcomes.

RHD*Weak D Type 38: A Family Study

AbstractAbstract 5155 Introduction:The RHD*weak D type 38 is produced by the single nucleotide change (833G>A) in RHD exon 6, carrying a Gly278Asp substitution in the transmembraneous RhD protein. This RHD allele shows a reduced expression of the D antigen on the red blood cell (RBC) surface and may be erroneously typed as D− by standard serologic methods, including the indirect antiglobulin test (IAT). The frequency of the RHD*weak D type 38 in Caucasians is reported to be 1. 5% in Ccee phenotype, while we have recently detected a relatively higher frequency of 2. 6% among Ccee phenotype in Brazil. In this study we performed a serologic and molecular analysis of three generations from a family with the rare RHD*weak D type 38. Study design and methods:The RBCs from 45 years-old woman blood donor tested D negative by routine serologic tests (Ccee phenotype) but were positive by the adsorption-elution technique. Further serologic investigation to establish the patterns of reactivity of the RBCs was preformed using anti-D Moabs IgM (clones HM10, P3X63, P3X21211F1, P3X21223B10; Diagast, Loos, France) and anti-D Moabs IgG/IAT (clones HM16, P3X35, P3X241, P3X249, P3X290; Diagast, Loos, France, and MS-26, ESD1; DiaMed, Latino América S. A.). Flow cytometric methods were employed to evaluate the D antigen densities, and molecular sequencing studies were done using a sequencing Kit (Big Dye Terminator v1. 1, applied Biosystems, Weiterstadt, Germany) and a genetic analyser (ABI 3100, Applied Biosystems, Foster City, CA, USA). Results:We found that the RBCs reacted negatively with 4/4 IgM anti-D, but showed weakly positive results with 4/7 IgG anti-D reagents. In face of such results we studied 12 members of her family and found that 6 more individuals tested D negative by standard serologic tests (Ccee phenotype) but were positive by adsorption-elution technique. The flow cytometry investigation of samples from the 7 subjects showed D antigen density in a range of 60 – 80 sites per cell and a Rhesus Index of 0. 1 – 0. 6. DNA sequencing analysis from 7 family members was performed showing that all descendants (siblings) had the same RHD*weak D type 38 genotype as the mother, also inherited by the grandson. Conclusions:The molecular analysis identified the presence of RHD*weak D type 38 in the three generations of a Brazilian family. The study revealed maternal inheritance (first generation) of the weak D type 38, with Ccee phenotype by her six children and the second generation showed paternal inheritance in a son. We also emphasize the significant prevalence of RHD*weak D type 38 in the Brazilian population, often showing a low antigen D density. Disclosures:No relevant conflicts of interest to declare.

Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype

Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype

Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging.

BackgroundAlzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.Methodology/Principal FindingsWe determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.Conclusions/SignificanceOur findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.

Spectinomycin resistance mutations in the rrn16 gene are new plastid markers in Medicago sativa

We report here the isolation of spectinomycin-resistant mutants in cultured cells of Medicago sativa line RegenSY-T2. Spectinomycin induces bleaching of cultured alfalfa cells due to inhibition of protein synthesis on the prokaryotic type 70S plastid ribosomes. Spontaneous mutants resistant to spectinomycin bleaching were identified by their ability to form green shoots on plant regeneration medium containing selective spectinomycin concentrations in the range of 25-50 mg/l. Sequencing of the plastid rrn16 gene revealed that spectinomycin resistance is due to mutations in a conserved stem structure of the 16S rRNA. Resistant plants transferred to the greenhouse developed normally and produced spectinomycin-resistant seed progeny. In light of their absence in soybean, a related leguminous plant, the isolation of spectinomycin-resistant mutants in M. sativa was unexpected. The new mutations are useful for the study of plastid inheritance, as demonstrated by detection of predominantly paternal plastid inheritance in the RegenSY-T2 × Szapko57 cross, and can be used as selective markers in plastid transformation vectors to obtain cisgenic plants.

Large‐scale asymmetric introgression of cytoplasmicDNAreveals Holocene range displacement in a North American boreal pine complex

Jack pine (Pinus banksiana) and lodgepole pine (Pinus contorta var. latifolia) are two North American boreal hard pines that hybridize in their zone of contact in western Canada. The main objective of this study was to characterize their patterns of introgression resulting from past and recent gene flow, using cytoplasmic markers having maternal or paternal inheritance. Mitochondrial DNA (mtDNA) and chloroplast DNA (cpDNA) diversity was assessed in allopatric populations of each species and in stands from the current zone of contact containing morphological hybrids. Cluster analyses were used to identify genetic discontinuities among groups of populations. A canonical analysis was also conducted to detect putative associations among cytoplasmic DNA variation, tree morphology, and site ecological features. MtDNA introgression was extensive and asymmetric: it was detected in P. banksiana populations from the hybrid zone and from allopatric areas, but not in P. contorta populations. Very weak cpDNA introgression was observed, and only in P. banksiana populations. The mtDNA introgression pattern indicated that central Canada was first colonized by migrants from a P. contorta glacial population located west of the Rocky Mountains, before being replaced by P. banksiana migrating westward during the Holocene. In contrast, extensive pollen gene flow would have erased the cpDNA traces of this ancient presence of P. contorta. Additional evidence for this process was provided by the results of canonical analysis, which indicated that the current cpDNA background of trees reflected recent pollen gene flow from the surrounding dominant species rather than historical events that took place during the postglacial colonization.

The Effect of Trp53 Gene-Dosage and Parent-of-Origin of Inheritance on Mouse Gamete and Embryo Function In Vitro1

The transformation-related protein 53 (TRP53) has a canonical role as the "guardian of the genome," serving to protect against the propagation of cells with genomic damage. Autocrine trophic signals act to block the accumulation of TRP53 in the normal preimplantation embryo. Culture of the early embryo at limiting dilutions in simple defined media limits autocrine signaling, resulting in the accumulation of TRP53. This TRP53 reduces the rate of development of embryos. In this study we show that deletion of the Trp53 gene improved development in vitro in a dose-dependent manner. Development to morphological blastocysts increased as the dose of Trp53 was reduced, and this was accompanied by a Trp53-dependent increase in the allocation of cells to the inner cell mass. The intermediate developmental response of heterozygous mice provides evidence for haploinsufficiency of this trait. This haploinsufficiency was evident irrespective of the parent-of-origin of the null allele; however, zygotes with paternal inheritance of the Trp53-null allele had better development in vitro than those with maternal inheritance. There was a beneficial effect of the Trp53-null allele on the number of oocytes released by Trp53(+/-) females, and heterozygous males produced higher fertilization rates than controls, although this was independent of the genotype of the fertilizing sperm. The study shows that ovulation induction or culture of embryos in limiting conditions creates conditions that favor the early development of embryos inheriting loss of Trp53 function. This occurs even in the heterozygous state, showing that the conditions provide a potential basis for accelerated accumulation of deleterious mutations within a population.

The large granular lymphocytic leukemia registry: A detailed analysis of 79 patients with LGL leukemia and rheumatoid arthritis.

6590 Background: The purpose of this study is to analyze patients enrolled in the LGL leukemia registry to distinguish the similarities between LGL leukemia and rheumatoid arthritis in order to access overlapping immune mechanisms that may be responsible for neutrophil mediated destruction. Methods: A retrospective chart review was performed on 79 patients enrolled in the LGL registry at Penn State Cancer Institute. All patients enrolled in the study had a diagnosis of both rheumatoid arthritis and potentially LGL leukemia. Data was collected for age, sex, RF factor positivity, family history, autoimmune disease, T-cell receptor gene rearrangement, and bone marrow invasion. Results: Of 79 patients the mean age of onset for LGL leukemia was 60 years old with no discrepancy noted between sexes, 37 M, 42 F. 49 patients were positive for rheumatoid factor. 27 patients had rheumatoid arthritis in a first degree relative with no discrimination between maternal or paternal inheritance. 22 patients were positive for any other autoimmune process. 60 patients were positive for T-cell receptor gene rearrangement. Of the remaining 19 patients that were negative for T-cell receptor rearrangement, 12 had evidence of bone marrow invasion (CD3/CD8+ infiltrate in &gt;20% bone marrow) and two showed bone marrow invasion of NK cell LGL (CD3/CD8-, CD57+) (Table). Conclusions: Patients with T cell LGL leukemia and rheumatoid arthritis appear to be clinically similar with regard to age, duration of disease, and other autoimmune disorders as patients with rheumatoid arthritis alone. Our patient population showed those with TLGL and RA also tends to have a positive family history of RA in up to 20% as opposed to 5-10% in RA patients. Given that RA and TLGL have a significantly higher expression of the HLA-DR4 haplotype than healthy patients, it is conceivable that with shared genetic alterations, and gene environment interactions that may promote posttranslational modification, there may be a loss of tolerance resulting in T cell activation, and eventual transformation into a T cell clone. [Table: see text]

PARENTAL GENETIC EFFECTS IN A CAVEFISH ADAPTIVE BEHAVIOR EXPLAIN DISPARITY BETWEEN NUCLEAR AND MITOCHONDRIAL DNA

Epigenetic parental genetic effects are important in many biological processes but their roles in the evolution of adaptive traits and their consequences in naturally evolving populations remain to be addressed. By comparing two divergent blind cave-dwelling cavefish populations with a sighted surface-dwelling population (surface fish) of the teleost Astyanax mexicanus, we report here that convergences in vibration attraction behavior (VAB), the lateral line sensory receptors underlying this behavior, and the feeding benefits of this behavior are controlled by parental genetic effects, either maternal or paternal inheritance. From behavioral studies and mathematical evolutionary simulations, we further demonstrate that disparity in nuclear and mitochondrial DNA in one of these cavefish populations that has hybridized with surface fish can be explained by paternal inheritance of VAB. The results suggest that parental genetic effects in adaptive behaviors may be important factors in biasing mitochondrial DNA inheritance in natural populations that are subject to introgression.

Abstract 3673: Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.

Abstract In SDHD mutation families, paragangliomas and pheochromocytomas usually occur only after paternal transmission of the mutation. This important but unexplained parent-of-origin effect is not due to imprinting of SDHD itself, as was initially suspected, since SDHD is biallelically expressed in several tissues. In clinically affected individuals who possess a paternally inherited SDHD mutation, there is loss of the entire maternal chromosome 11 in tumour DNA, implying that tumorigenesis requires loss of not only maternal (wild type) SDHD but also a further, imprinted, tumor suppressor gene (TSG). We report the second case of an SDHD-related tumor (a pheochromocytoma in a 33 year old woman possessing the common pathogenic mutation, p.Pro81Leu) occurring after maternal transmission. It is the first reported investigation of tumor DNA in this situation. Tumor DNA revealed loss of heterozygosity (LOH) at paternal 11q23 causing loss of the wild-type SDHD allele and also LOH affecting maternal 11p15, including H19. These two LOH regions were separated by a region exhibiting clearly retained heterozygosity, containing SDHAF2 (a recently reported paraganglioma TSG), which therefore appears uninvolved here. This case provides strong molecular evidence that the tumorigenic requirement for maternal 11p15 loss (in addition to inactivation of both SDHD alleles) drives the observed parent-of-origin effect. Thus, SDHD-related tumorigenesis most likely involves a “three-hit” mechanism that includes (as one of the hits) loss of an imprinted (paternally silenced and maternally active) TSG from chromosome 11, such as H19). Tumor formation more commonly results from paternal inheritance of SDHD mutations, as the necessary loss of both the wild type SDHD allele and maternal 11p15 can then occur by a single event (loss of maternal chromosome 11). These findings have important implications regarding the clinical management of carriers of maternally inherited SDHD mutations, who we confirm can develop pheochromocytomas, and the understanding of the parent-of-origin effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3673. doi:1538-7445.AM2012-3673

An Unexpected Function of the Prader-Willi Syndrome Imprinting Center in Maternal Imprinting in Mice

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11–q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings open the opportunity for a novel approach to the treatment of PWS.

New Mutations at the Imprinted Gnas Cluster Show Gene Dosage Effects of Gsα in Postnatal Growth and Implicate XLαs in Bone and Fat Metabolism but Not in Suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism.

Huntington's like conditions in China, A review of published Chinese cases.

Background: Knowledge about HD in China is lacking in the international literature. We have therefore analyzed the Chinese literature to thoroughly explore the clinical characteristics of Huntington disease in China.Methods: A computer-based online search of China National Knowledge Infrastructure was performed to review case reports concerning HD published between January 1980 and April of 2011, and the clinical characteristics were extracted.Results: A total of 92 studies involving 279 patients (157 males and 122 females) were collected, 82.0% of which were from provinces of North China. Most of the cases (97.8%) had a family history of HD, and paternal inheritance (65.5%) was higher than maternal inheritance (34.5%). Onset age was 35.8 (± 11.8) years, death occurred with 45.6 (± 13.5) years after a course of 11.6 (± 5.6) years. Involuntary movements were the most frequent reported presentation (found in 52.3%, including 64.4% in the entire body, 19.8% in the upper limbs, and 13.7% in the head and face). Psychiatric symptoms at onset were reported in 16.1%, and cognitive impairment in 1.8%. With disease progression, 99.6% of patients had abnormal movements, 67.9% cognitive impairment, and 35.0% suffered psychiatric symptoms. Of the reported patients, only 22 underwent IT15 gene testing with positive results.Conclusion: HD is a well-reported entity in Chinese medical literature, however, only a small number of instances have been proven by molecular diagnosis. Most of the features resemble what is known in other countries. The highly predominant motor presentation, and the higher male prevalence as well as the apparent concentration in Northern China may be due to observational bias. There is therefore a need to prospectively examine cohorts of patients with appropriate comprehensive assessment tools including genetic testing.

The identification of quantitative trait loci that control the paternal inheritance of a mitochondrial plasmid in rapeseed (&lt;i&gt;Brassica napus &lt;/i&gt;L.)

Some varieties of Brassica napus (rapeseed) and B. rapa contain a liner mitochondrial plasmid that is unique in that it can be inherited from the male parent through the pollen. We found that two rapeseed cultivars, Norin 16 and Westar, showed different rates of plasmid inheritance from the paternal parent (78.8% and 27.5%, respectively). To identify nuclear genes controlling the inheritance of the plasmid, we carried out quantitative trait locus (QTL) analyses using F(2) populations derived from a cross between these two cultivars. The F1 plants transmitted the plasmid from the paternal plant at a frequency of approximately 60%; the transmission rates of the F2 lines varied greatly, from 0 to 100%, with an average of 68.2%. A genetic map was constructed based on the segregation of 175 loci in the 102 F2 plants. A total of 22 linkage groups were obtained, all of which could be assigned to the 19 rapeseed chromosomes. The total map length was 1374.7 cM, with an average distance of 7.9 cM between the markers. We found that three quantitative trait loci for plasmid paternal transfer, qPpt1, qPpt2 and qPpt3, located on chromosomes A5, C2 and C9, respectively, were significantly linked to the transmission frequency, whose the logarithm of odds (LOD) score were 4.97, 3.49 and 3.57, respectively. Their explained phenotypic variances were 25.0%, 22.2% and 37.1%, respectively. These results suggest that the paternal inheritance of the mitochondrial plasmid is controlled by a relatively small number of nuclear genes.

P2-13-02: Parent of Origin of BRCA Mutation May Determine Age at Breast Cancer Diagnosis.

Abstract Background: Genetic diseases may display parent-of-origin effects. In such cases, the risk depends on the specific parent or origin allele. Imprinting effect is evident in autosomal dominant hereditary paraganglioma leads to tumors only if inherited from paternal germline. Cancer penetrance in mutations carriers may be determined by the parent origin of BRCA mutation. Methods: From 2007–2010 we analyzed 1889 consecutive (136 ovarian + 1753 breast) breast (BrCa) or ovarian cancer (OvCa) patients presenting for treatment at our outpatient facility. In 130 patients with BRCA 1 or 2 mutations the parent of origin for the mutation was known. Of the 130 patients 2 had both BRCA1 and BRCA2 mutated paternally inherited and were excluded from this analysis. Of the breast cancer patients: 28 patients had paternal and 29 had maternal BRCA1 mutations, 24 had paternal and 21 had maternal BRCA 2 mutations. Of the ovarian cancer patients 6 had paternal and 10 had maternal BRCA1 mutations, 7 had paternal and 3 had maternal BRCA2 mutations. In carriers of BRCA mutations the mean age at diagnosis for ovarian cancer was 51 (range 21–70) and for breast cancer was 43 (range 24–78). Two-sample t-test was used to compare the mean age at diagnosis in patients with BRCA 1 or 2 mutations of paternal or maternal inheritance. For breast cancer maternal allele versus paternal allele 2-sample t-test and p-value were compared for the age at first diagnosis. For breast cancer patients BRCA1 maternal inheritance (mean+SD yrs) 45.73+11.22 versus paternal inheritance 38.04+7.14 2-sample t-test p-value p&amp;lt;0.0020. For breast cancer BRCA2 maternal inheritance (mean+SD yrs) 50.65+10.44 versus paternal inheritance 41.68+6.16, 2-sample t-test p-value p&amp;lt;0.0008. Results: Significantly younger age at breast cancer diagnosis was observed in paternal vs. maternal inheritance of BRCA1 mutation (38 vs 46, respectively, p&amp;lt;0.0020) and BRCA2 mutation (42 vs 51 respectively, p&amp;lt;0.0008). There was no significant difference between paternal and maternal age of ovarian cancer diagnosis of BRCA1 (p&amp;lt;0.1415) or BRCA2 mutation (p&amp;lt;0.3470). Conclusion: The restrospective nature of the study may introduce ascertainment bias. However, the breast and ovarian cancers cases in BRCA1 &amp; 2 carriers with maternal or paternal inheritance mirror the Mendelian autosomal dominant pattern in our unselected consecutive cohort of patients. Maternal and paternal inherited BRCA alleles may not be exchangeable. Women with paternally inherited mutations in BRCA gene mutations develop breast cancer at younger age compared with women who inherit the gene mutations from their mothers. In this small sample, clear differences at age of cancer diagnosis are apparent in paternal inheritance of BRCA gene mutation. If this observation duplicates in larger cohorts results will have important implications for recommendation of surgical risk reduction in BRCA mutation carriers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-13-02.

Paternal leakage of mitochondrial DNA in experimental crosses of populations of the potato cyst nematode Globodera pallida

Animal mtDNA is typically assumed to be maternally inherited. Paternal mtDNA has been shown to be excluded from entering the egg or eliminated post-fertilization in several animals. However, in the contact zones of hybridizing species and populations, the reproductive barriers between hybridizing organisms may not be as efficient at preventing paternal mtDNA inheritance, resulting in paternal leakage. We assessed paternal mtDNA leakage in experimental crosses of populations of a cyst-forming nematode, Globodera pallida. A UK population, Lindley, was crossed with two South American populations, P5A and P4A. Hybridization of these populations was supported by evidence of nuclear DNA from both the maternal and paternal populations in the progeny. To assess paternal mtDNA leakage, a ~3.4kb non-coding mtDNA region was analyzed in the parental populations and in the progeny. Paternal mtDNA was evident in the progeny of both crosses involving populations P5A and P4A. Further, paternal mtDNA replaced the maternal mtDNA in 22 and 40% of the hybrid cysts from these crosses, respectively. These results indicate that under appropriate conditions, paternal leakage occurs in the mtDNA of parasitic nematodes, and supports the hypothesis that hybrid zones facilitate paternal leakage. Thus, assumptions of strictly maternal mtDNA inheritance may be frequently violated, particularly when divergent populations interbreed.

Membrane-associated RING-CH 10 (MARCH10 Protein) Is a Microtubule-associated E3 Ubiquitin Ligase of the Spermatid Flagella

Spermiogenesis is a complex and dynamic process of the metamorphosis of spermatids into spermatozoa. There is a great deal that is still unknown regarding the regulatory mechanisms for the formation of the sperm flagellum. In this study, we determined that the membrane-associated RING-CH 10 (March10) gene is predominantly expressed in rat testis. We isolated two March10 isoforms encoding MARCH10a and MARCH10b, which are generated by alternative splicing. MARCH10a is a long RING finger protein, and MARCH10b is a short RING finger-less protein. Immunohistochemical staining revealed that the MARCH10 proteins are specifically expressed in elongating and elongated spermatids, and the expression is absent in epididymal spermatozoa. MARCH10 immunoreactivity was observed in the cytoplasmic lobes as well as the principal piece and annulus of the flagella. When overexpressed in COS7 cells, MARCH10a was localized along the microtubules, whereas MARCH10b was distributed throughout the cytoplasm. An in vitro microtubule cosedimentation assay showed that MARCH10a is directly associated with microtubules. An in vitro ubiquitination assay demonstrated that the RING finger domain of MARCH10a exhibits an E3 ubiquitin ligase activity along with the E2 ubiquitin-conjugating enzyme UBE2B. Moreover, MARCH10a undergoes proteasomal degradation by autoubiquitination in transfected COS7 cells, but this activity was abolished upon microtubule disassembly. These results suggest that MARCH10 is involved in spermiogenesis by regulating the formation and maintenance of the flagella in developing spermatids.