Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome.

Livestock populations can be used to study recessive defects caused by deleterious alleles. The frequency of deleterious alleles including recessive lethal alleles can stay at high or moderate frequency within a population, especially if recessive lethal alleles exhibit an advantage for favourable traits in heterozygotes. In this study, we report such a recessive lethal deletion of 212kb (del) within the BBS9 gene in a breeding population of pigs. The deletion produces a truncated BBS9 protein expected to cause a complete loss-of-function, and we find a reduction of approximately 20% on the total number of piglets born from carrier by carrier matings. Homozygous del/del animals die mid- to late-gestation, as observed from high increase in numbers of mummified piglets resulting from carrier-by-carrier crosses. The moderate 10.8% carrier frequency (5.4% allele frequency) in this pig population suggests an advantage on a favourable trait in heterozygotes. Indeed, heterozygous carriers exhibit increased growth rate, an important selection trait in pig breeding. Increased growth and appetite together with a lower birth weight for carriers of the BBS9 null allele in pigs is analogous to the phenotype described in human and mouse for (naturally occurring) BBS9 null-mutants. We show that fetal death, however, is induced by reduced expression of the downstream BMPER gene, an essential gene for normal foetal development. In conclusion, this study describes a lethal 212kb deletion with pleiotropic effects on two different genes, one resulting in fetal death in homozygous state (BMPER), and the other increasing growth (BBS9) in heterozygous state. We provide strong evidence for balancing selection resulting in an unexpected high frequency of a lethal allele in the population. This study shows that the large amounts of genomic and phenotypic data routinely generated in modern commercial breeding programs deliver a powerful tool to monitor and control lethal alleles much more efficiently.

Pink1 kinase and its membrane potential (Deltaψ)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode.

The Parkinson disease-associated kinase Pink1 is targeted to mitochondria where it is thought to regulate mitochondrial quality control by promoting the selective autophagic removal of dysfunctional mitochondria. Nevertheless, the targeting mode of Pink1 and its submitochondrial localization are still not conclusively resolved. The aim of this study was to dissect the mitochondrial import pathway of Pink1 by use of a highly sensitive in vitro assay. Mutational analysis of the Pink1 sequence revealed that its N terminus acts as a genuine matrix localization sequence that mediates the initial membrane potential (Δψ)-dependent targeting of the Pink1 precursor to the inner mitochondrial membrane, but it is dispensable for Pink1 import or processing. A hydrophobic segment downstream of the signal sequence impeded complete translocation of Pink1 across the mitochondrial inner membrane. Additionally, the C-terminal end of the protein promoted the retention of Pink1 at the outer membrane. Thus, multiple targeting signals featured by the Pink1 sequence result in the final localization of both the full-length protein and its major Δψ-dependent cleavage product to the cytosolic face of the outer mitochondrial membrane. Full-length Pink1 and deletion constructs resembling the natural Pink1 processing product were found to assemble into membrane potential-sensitive high molecular weight protein complexes at the mitochondrial surface and displayed similar cytoprotective effects when expressed in vivo, indicating that both species are functionally relevant.

Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene.

We describe a case of neonatal diabetes due to a homozygous mutation (c.3 G>T) at the INS gene, leading to lack of insulin expression and severe hyperglycemia from day one of life requiring permanent insulin replacement therapy. The genetic loss of endogenous insulin production likely led to lack of immune tolerance to insulin, with resultant autoantibody production against exogenous insulin and progressive immune-mediated lipoatrophy at injection sites.

MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival.

The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.

[Linkage analysis of six Algerian families with autosomal recessive non specific mental retardation]. / Analyse génétique de six familles Algériennes avec retard mental non spécifique autosomique récessif.

BACKGROUND: Mental retardation is one of the most frequent major handicap, with a 1-3 % frequency in the general population. The recent progress of molecular biology and cytogenetic allowed to identify new genes for non syndromic autosomal recessive mental retardation. AIM: To seek a genetic linkage to the loci implied in the nonspecific mental retardation transmitted into autosomal recessive (ARNSMR) in Algerian families with several affected members and to make the Genetic analysis of ARNSMR for 4 known loci: 3p25-pter; 4q24- q25, 19p13.12 and 1p21.1-p13. METHODS: The study concerned 34 individuals including 15 patients, belonging to six consanguineous Algerian families. Genotyping was made using polymorphic microsatellite markers and the analysis carried out thanks to the program Gene Mapper software. Statistical analyses were validated using the Fast Link programme of the Easy linkage software (V4:00 betas). RESULTS: The study carried out made it possible to exclude linkage of all loci for 3 families, nevertheless the linkage of one family to the locus 1p21.1-p13.3 remains possible. CONCLUSION: The absence of linkage of 4 Algerian families with autosomal recessive mental retardation to 3 well known loci, confirms the genetic heterogeneity of mental retardation. We have to pursue research of candidate genes by whole genome scan.

Genetics of hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSPs) are clinically and genetically highly heterogeneous. The key symptom of spastic paraparesis of lower limbs can be complicated by a variety of signs and symptoms including cognitive impairment, optic atrophy, cerebellar ataxia, peripheral nerve involvement, or seizures. At least 48 loci have been identified, termed SPG1-SPG48. Ten genes for autosomal dominant HSP are currently known, SPG4 being by far the most common subtype accounting for ∼50% of cases. SPG3 is especially common in young-onset cases. Autosomal recessive HSP seems to be even more heterogeneous. The known 12 autosomal recessive HSP genes collectively explain about one third of cases only. The most common causes for pure autosomal recessive HSP are SPG7 and SPG5. Mental retardation and thin corpus callosum on magnetic resonance imaging point toward SPG11 and SPG15. The authors provide an overview on clinical, neurophysiologic, and neuroradiologic characteristics of the more common HSP subtypes. More details are given in the tables for quick reference, and a genetic testing strategy is proposed.

Exclusion of candidate genes in seven Turkish families with autosomal recessive amelogenesis imperfecta.

Amelogenesis imperfectas (AI) are a group of inherited defects of dental enamel formation that show both clinical and genetic heterogeneity. Seven Turkish families segregating autosomal recessive AI (ARAI) were evaluated for evidence of a genetic etiology of AI for the seven major candidate gene loci (AMBN, AMELX, ENAM, FAM83H, KLK4, MMP20, and TUFT1). Dental and periodontal characteristics of the affected members of these families were also described. The mean scores of DMFS and dfs indices were 9.7 and 9.6, respectively. The mean PPD was 2.2 mm and the percentage of the sites with plaque and BOP were 87.8% and 72.4%, respectively. The exons and intron/exon junctions of the candidate genes were sequenced and no gene mutations were identified in any individuals. These findings support the existence of an additional gene(s) that are etiologic for ARAI in these families.

[Impairment of homologous chromosome synapsis in meiosis in rye Secale cereale L. caused by a recessive mutation of the sy18 gene].

AExpression and inheritance of the sy18 mutation causing impairment of synapsis homology were studied. It was established that the abnormal phenotype is determined by a recessive allele of the sy18 gene. Univalents and multivalents are observed in homozygotes for this mutant allele. According to the electron microscopic analysis of synaptonemal complexes in mutants, homologous synapsis occurs together with nonhomologous synapsis. The sy18 gene was found to have no allelism with asynaptic genes sy1 and sy9 and with genes sy10 and sy19 causing, like sy18, disturbances in synapsis homology.

Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement.

CONTEXT: Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality. OBJECTIVE: Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement. DESIGN: TNSALP enzyme and substrate analysis and TNSALP mutation analysis were performed on all family members. PATIENTS: A boy with HPP showing long bone deformity that spontaneously improved in utero and after birth is described. His older brother has the childhood form of HPP without findings until after infancy. His parents and twin sister are clinically unaffected. RESULTS: Both boys are compound heterozygotes for the same missense mutations in TNSALP, documenting autosomal recessive inheritance for their HPP. The parents each carry one defective allele. CONCLUSIONS: The patient is an autosomal recessive case of HPP with prenatal long bone deformity but with spontaneous prenatal and postnatal improvement. Thus, prenatal detection by sonography of bowing of long bones from HPP, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the TNSALP defect(s).

Detection of a true breeding homeotic gene mutant Pps-1 with partially petaloid sepals in opium poppy (Papaver somniferum L.) and its genetic behavior.

A spontaneous true breeding homeotic gene mutant Pps-1 with distinct partial petaloid sepals was detected in the population of downy mildew (DM)-resistant elite accession I-14 during our studies for the identification of disease resistance sources in opium poppy. The trait was found to be stable and inherited truly in the subsequent generations. Genetic studies were carried out through systematic reciprocal crosses with the parental wild-type genotype I-14, and segregation pattern of phenotypic characteristics in F(1) and F(2) populations clearly indicated single recessive nuclear gene control of the mutant character. The studies have demonstrated that the mutant phenotype is due to mutations at the Pps-1 locus that possibly corresponds to B-class function (according to ABC model) with negative control function. The mutant Pps-1 being single-whorl homeotic mutant might greatly help in providing insight into mechanisms of flower development in opium poppy.

Autosomal dominant inheritance of centrotemporal sharp waves in rolandic epilepsy families.

PURPOSE: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well-designed family segregation analysis study. METHODS: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4-16 years underwent sleep-deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two independent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage. RESULTS: Thirty siblings from 23 families underwent EEG examination. Twenty-three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27-0.69). The male to female ratio of CTS affectedness was approximately equal. CONCLUSIONS: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X-linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy.

A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.

Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders.

Evidence for "Unertan Syndrome" and the evolution of the human mind.

A new family exhibiting "Unertan Sydnrome" was discovered. The pedigree analysis showed marriages between relatives. This family was similar to the first one (see Tan, 2006a), providing a firm evidence for the new syndrome. The affected children showed habitual quadrupedal walking gait, that is, they walked on wrists and feet with straight legs and arms. Their heads and bodies were mildly flexed; they exhibited mild cerebellar signs, and severe mental retardation. The pedigree demonstrated a typical autosomal-recessive inheritance. The genetic nature of this syndrome suggests a backward stage in human evolution (devolution), which would be consistent with theories of punctuated evolution. The results reflected a new theory on the evolution of human beings. That is, the evolution of humans would in fact be the evolution of the extensor motor system, responsible for upright posture, against the gravitational forces. This would be coupled with the emergence of the human mind, which can be considered a reflexion of the human motor system, in accord with the psychomotor theory (see Tan, 2005a). The most important characteristic of the newly emerged human mind was the resistance against gravitational forces. This was the resistive mind, the origins of human creativity.

Accumulation of recessive lethal mutations in Saccharomyces cerevisiae mlh1 mismatch repair mutants is not associated with gross chromosomal rearrangements.

We examined mismatch repair (MMR)-defective diploid strains of budding yeast grown for approximately 160 generations to determine whether decreases in spore viability due to the uncovering of recessive lethal mutations correlated with an increase in gross chromosomal rearrangements (GCRs). No GCRs were detected despite dramatic decreases in spore viability, suggesting that frameshift and/or other unrepaired DNA replication lesions play a greater role than chromosomal instability in decreasing viability in MMR-defective strains.

SNP-SNP interactions in breast cancer susceptibility.

BACKGROUND: Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. METHODS: In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. RESULTS: None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. CONCLUSION: The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management.

Promoter mutations of an essential gene for pollen development result in disease resistance in rice.

Disease resistance and sexual reproductive development are generally considered as separate biological processes, regulated by different sets of genes. Here we show that xa13, a recessive allele conferring disease resistance against bacterial blight, one of the most devastating rice diseases worldwide, plays a key role in both disease resistance and pollen development. The dominant allele, Xa13, is required for both bacterial growth and pollen development. Promoter mutations in Xa13 cause down-regulation of expression during host-pathogen interaction, resulting in the fully recessive xa13 that confers race-specific resistance. The recessive xa13 allele represents a new type of plant disease resistance.

Phenylthiocarbamide perception in patients with schizophrenia and first-degree family members.

OBJECTIVE: The inability to taste phenylthiocarbamide (PTC) has been associated with medical and neurological illnesses not typically related to taste. The authors examined PTC sensitivity in schizophrenia patients and their non-ill relatives to determine whether this represented a vulnerability marker. METHOD: PTC sensitivity was assessed in 42 schizophrenia patients, 23 healthy comparison subjects, and 12 first-degree relatives of the patients. RESULTS: More nontasters were found among patients and family members than healthy comparison subjects. Among patients, nontasters had more positive symptoms. Differences were not explained by sex, age, medication, smoking, or cognitive impairment. CONCLUSIONS: The prevalence of PTC nontasters was greater among schizophrenia patients and non-ill first-degree family members. Phenotypic variation in PTC sensitivity is genetic in origin. This suggests a higher risk for illness among subjects with recessive alleles.

Inheritance of a recessive transgene-associated character controlling albinism in transgenic bean (Phaseolus vulgaris L.).

We identified a transgenic line exhibiting albinism during our work to introduce genes through genetic engineering in dry bean (Phaseolus vulgaris). The transgenic mother plant (R0) presented a normal phenotype and generated albino and normal green plants in the first generation (R1). The segregation ratio of the albino character in the R1 and R2 generations fitted the expected ratio for a character controlled by a single recessive gene linked to a foreign gus gene, suggesting that albinism could be a consequence of insertional mutation caused by introduction of the exogenous gene. Analysis by electron microscope revealed that the albino cells possessed no chloroplasts and a greater number of mitochondria when compared to normal green plants. This transgenic bean line may be used in understanding the genetic control of chloroplast genesis, for acquiring additional knowledge of genomic structure or in physiological studies. This is the first described transgene-associated mutant bean plant.

Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance.

Oculodentodigital dysplasia (ODDD) is a rare inherited disorder affecting the development of the face, eyes, teeth, and limbs. The majority of cases of ODDD are inherited as an autosomal dominant condition. There are few reports of probable autosomal recessive transmission. Affected patients exhibit a distinctive physiognomy with a narrow nose, hypoplastic alae nasi, and anteverted nostrils, bilateral microphthalmos, and microcornea. Sometimes iris anomalies and secondary glaucoma are present. There are malformations of the distal extremities such as syndactyly. In addition, there are defects in the dental enamel with hypoplasia and yellow discoloration of the teeth. Less common features include hypotrichosis, intracranial calcifications, and conductive deafness secondary to recurrent otitis media. We describe three brothers with ODDD. Their parents are first cousins and present no features of ODDD. These data are in favor of autosomal recessive inheritance and suggest genetic heterogeneity for this entity.