A genetic model for age at onset in Huntington disease.

Although numerous investigators have confirmed excess paternal transmission among juvenile-onset cases of Huntington disease (HD), there are conflicting reports that the late-onset form is inherited more often from the mother than from the father. Results from a survey of age at onset and age at death in 569 patients corroborate earlier findings of delayed onset of HD among offspring of affected mothers at both ends of the onset-age spectrum: 23 of 28 juvenile-onset offspring had affected fathers, and there were 1.6 times more late-onset offspring born to affected mothers than to affected fathers. These patterns, together with data that link age-at-onset variability to familial longevity trends, suggest a model where age at onset is governed, generally, by a set of independently inherited aging genes, but expression of the HD gene may be significantly delayed in individuals who possess a particular maternally transmitted factor.     

Huntington disease in Georgia: age at onset.

Age at onset of motor symptoms was collected on 611 persons affected with Huntington disease (HD) among 3,201 persons "at risk" in 108 kindreds. Life-table estimates correcting for truncated intervals of observation (censoring) produced a median age at onset 5 years older than the observed mean. Risk estimates of HD onset for persons at risk, as calculated by life-table methods, were significantly higher for older ages than were estimates based on the observed distribution of onsets. Age-specific incidence was found to be highest at age 35-64 years, a considerably older age interval than suggested by previous estimates. The offspring of affected males had significantly younger onset than did offspring of affected females, and a trend suggesting and excess of paternal descent among juvenile-onset cases was present. Life-table analysis is contrasted with analyses of (a) the observed distribution of age at onset and (b) remote cohorts age 63 or older at the time of data collection. The implications for risk prediction, genetic counseling, and genetic analysis of HD are discussed.     

Factors related to onset age of Huntington disease.

One prominent feature of Huntington disease (HD) is the variable age at which the characteristic neurological or psychiatric symptoms appear. Ages of manifestation varying from 4 to 65 years are found in a sample of 95 HD pedigrees compiled since 1968 from the Southeastern United States. Significant parent-child correlations of age of onset indicate consistency of onset age within nuclear families. However, an average intrafamily range of 9 years and an average intrapedigree range of 12 years reveal substantial variability of onset age within these groups. Of the nine cases of juvenile-onset HD identified in this sample, seven were of paternal descent. The preponderance of juvenile patients inheriting the HD gene from a father confirms similar findings from other studies. In addition, a trend toward earlier onset in all offspring of paternal transmission suggests that the juvenile-onset phenomenon is only the tail of a shift in the curve of onset ages for this group. A trend toward earlier onset in successive generations was noted. This "anticipation" may reflect the finding that persons of early onset in prior generations are selectively nonreproductive as a result of manifestation of the disorder. By identifying familial factors influencing onset age of HD, it may be possible to more effectively evaluate environmental factors that influence the onset of the disorder.     

Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting.

It is well recognized that age at onset of Huntington disease (HD) is strongly influenced by the sex of the affected parent, and this has lead to suggestions that genetic imprinting or maternal specific factors may play a role in the expression of the disease. This study evaluated maternal and paternal ages, birth order, parental age at onset, and sex of the affected parent and grandparent in 1,764 patients in the National HD Roster by using linear-regression techniques which incorporated a weighted least-squares approach to accommodate the correlation among siblings. It was found that paternal age is negatively associated with age at onset of HD, particularly among subjects who inherit the mutant gene from grandfathers. Apparent associations between age at onset and birth order and between age at onset and maternal age were not significant after adjustment for paternal age. The paternal age effect is strongest among juvenile-onset cases and individuals with anticipation of greater than or equal to 10 years, although it is detectable across the entire age-at-onset distribution. The tendency for older fathers, including those not transmitting the HD gene, to have affected offspring with early-onset disease may be consistent with a gene imprinting mechanism involving DNA methylation. Because paternal age in unaffected fathers is also a significant determinant of age at onset, methylation in this context might involve HD modifier genes or the normal HD allele.     

A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h²=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21–23 (LOD=2.29), and 6q24–26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.     

Maternal factors in onset of Huntington disease.

Analyses of father-offspring and mother-offspring similarity in onset age suggest that nuclear genes account for a significant portion of the modification of onset age in Huntington disease. The effects of non-nuclear modifiers are supported by the finding that the offspring of affected women have significantly older mean ages of onset than offspring of affected men irrespective of the onset age in the parent. The absence of increased father-daughter similarity indicates that modification is not X-linked. The absence of reproductive advantage for late-onset individuals and the absence of a multigenerational maternal-lineage effect suggest that the modifying effect of the sex of the affected parent occurs in a single parental generation. Offspring of affected women with onset between ages 35 and 49 had a significantly older mean onset age than their mothers. This suggests that a protective effect may be conferred upon the offspring of affected women.     

NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner

In addition to the pathogenetic CAG repeat expansion other genetic factors play a significant role in determining age at onset (AO) in Huntington disease (HD), e.g. variations in the NR2A and NR2B glutamate receptor subunit genes (GRIN2A, GRIN2B). In order to expand these findings we fine-mapped a larger HD patient panel (n = 250) using densely spaced markers flanking the originally associated SNPs in GRIN2A and GRIN2B. In GRIN2A association fine-mapping based on eight additional SNPs confirmed intron 2 as the region of strongest association. In GRIN2B fine-mapping with seven additional SNPs consolidated C2664T as causal genetic variation. Gender stratification of patients revealed differences in the variability in AO attributable to the CAG repeat number and highly significant differences in the AO association with the C2664T and rs8057394/ rs2650427 variations. Addition of the corresponding genotype variations to the effect of CAG repeat lengths resulted in a significant increase of the R ² values only in females. The sex-specific effect for C2664T is underscored by differences in the genotype and allele frequencies observed for female versus male HD patients (P = 0.01) caused by decreased CC frequency in females. Overall, female HD patients homozygous for the CC genotype tended to have later AO compared to the other two genotypes. Stratification of the results by presumed menopausal status demonstrated that the significant findings were predominantly observed in pre-menopausal patients. We speculate that altered hormone levels herald protective effects of this genotype. Together, GRIN2A and GRIN2B genotype variations explain 7.2% additional variance in AO for HD.     

The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease.

In a population at equilibrium for a sex-linked lethal, one-third of the genes for that lethal must arise anew each generation. Therefore, one-third of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, we have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be carriers. This result deviates significantly from expected (P less than .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband families, the deviation from expected was still significant (P less than .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be one-half (see Appendix). Of all 20 maternal grandmothers studied, five were +/+ and 15 were +/- (P less than .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In four of the five cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There appears to be a true deficiency of new mutatnts among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.     

Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease

Huntington disease (HD) is associated with an unstable trinucleotide CAG.CTG repeat expansion. Although the repeat length is inversely correlated with the age-at-onset of symptoms, variability between patients who have inherited the same HD repeat length clearly suggests that other factors influence this aspect of the disease. As repeat length profiles in somatic tissues suggest that repeat length gains may contribute to both the tissue-specificity and progressive nature of HD pathogenesis, genetic modifiers of mutation length variability may therefore influence the age-at-onset of the disease. Using a sensitive single molecule-PCR assay we show that HD mutation length profiles in buccal cell DNA vary from individual to individual. The resulting data provide the first quantitative evidence that inherited CAG.CTG repeat length has a major influence on somatic CAG.CTG repeat length variation. In addition, we confirm that further environmental and/or genetic modifiers of repeat length variation exist and discuss the implications that our results may have on understanding the factors that influence severity and age-at-onset of Huntington disease symptoms.     

The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.

We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset. These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus.     

A test of the hypothesis that correlational selection generates genetic correlations

Theory predicts that correlational selection on two traits will cause the major axis of the bivariate G matrix to orient itself in the same direction as the correlational selection gradient. Two testable predictions follow from this: for a given pair of traits, (1) the sign of correlational selection gradient should be the same as that of the genetic correlation, and (2) the correlational selection gradient should be positively correlated with the value of the genetic correlation. We test this hypothesis with a meta-analysis utilizing empirical estimates of correlational selection gradients and measures of the correlation between the two focal traits. Our results are consistent with both predictions and hence support the underlying hypothesis that correlational selection generates a genetic correlation between the two traits and hence orients the bivariate G matrix.     

Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle

To test the popular but unproven assumption that the metaphase-anaphase transition in vertebrate somatic cells is subject to a checkpoint that monitors chromosome (i.e., kinetochore) attachment to the spindle, we filmed mitosis in 126 PtK1 cells. We found that the time from nuclear envelope breakdown to anaphase onset is linearly related (r2 = 0.85) to the duration the cell has unattached kinetochores, and that even a single unattached kinetochore delays anaphase onset. We also found that anaphase is initiated at a relatively constant 23-min average interval after the last kinetochore attaches, regardless of how long the cell possessed unattached kinetochores. From these results we conclude that vertebrate somatic cells possess a metaphase-anaphase checkpoint control that monitors sister kinetochore attachment to the spindle. We also found that some cells treated with 0.3-0.75 nM Taxol, after the last kinetochore attached to the spindle, entered anaphase and completed normal poleward chromosome motion (anaphase A) up to 3 h after the treatment--well beyond the 9-48-min range exhibited by untreated cells. The fact that spindle bipolarity and the metaphase alignment of kinetochores are maintained in these cells, and that the chromosomes move poleward during anaphase, suggests that the checkpoint monitors more than just the attachment of microtubules at sister kinetochores or the metaphase alignment of chromosomes. Our data are most consistent with the hypothesis that the checkpoint monitors an increase in tension between kinetochores and their associated microtubules as biorientation occurs.     

The efficiency of folding of some proteins is increased by controlled rates of translation in vivo. A hypothesis

We propose that the way in which some proteins fold is affected by the rates at which regions of their polypeptide chains are translated in vivo. Furthermore, we suggest that their gene sequences have evolved to control the rate of translational elongation such that the synthesis of defined portions of their polypeptide chains is separated temporally. We stress that many proteins are capable of folding efficiently into their native conformations without the help of differential translation rates. For these proteins the amino acid sequence does indeed contain all the information needed for the polypeptide chain to fold correctly (even in vitro, after denaturation). However, other proteins clearly do not fold efficiently into their native conformation in vitro. We argue that the efficiency of folding of these problematic proteins in vivo may be improved by controlled synthesis of the nascent polypeptide.     

Genomic organization and characterization of mouse SAP, the gene that is altered in X-linked lymphoproliferative disease

X-linked lymphoproliferative (XLP) disease is a fatal immunological disorder that renders the immune system unable to respond effectively to Epstein-Barr virus (EBV) infection. The gene that encodes a protein termed SAP or SH2D1A is either deleted or mutated in XLP patients, resulting in uncontrolled B- and T-cell proliferation upon EBV infection. Here, we report the cloning and characterization of the mouse SAP gene. It is localized on the mouse X chromosome and comprises four exons spanning approximately 25 kb. Its expression appears to be restricted to T lymphocytes. Whereas a high level of SAP expression is observed in Thl cells, only small amounts are detectable in Th2 cells. Moreover, SAP expression is down-regulated upon in vitro activation of T cells, including CD4+, CD8+ single-positive T cells, and Thl and Th2 cells. This study provides valuable information for in-depth genetic and biochemical analysis of the function of SAP in the immune system.     

A test of the niche dimension hypothesis in an arid annual grassland

The niche dimension hypothesis predicts that greater numbers of limiting factors can allow greater numbers of species to coexist through species' tradeoffs for different limiting factors. A prediction that follows is that addition of multiple limiting resources to plant communities will increase productivity and simultaneously decrease diversity. Species loss due to limiting resource enrichment might occur through reducing the number of resources that species compete for or by changing the identity of limiting factors. We tested these predictions of the niche dimension hypothesis in an arid annual grassland by adding combinations of nutrients: nitrogen (N), phosphorus (P), and potassium with other elements (O). We found that species number decreased while biomass increased with greater numbers of added resources. In particular, N in combinations with P or O resulted in the greatest species loss, while biomass increased super-additively with N and P together. The addition of greater numbers of added nutrients decreased the availability of light and soil moisture, consistent with a potential shift in the identity of limiting resources. Species also differed in their responses to different combinations of N, P, and O, supporting predictions of resource-ratio tradeoffs. These results are particularly notable because this experiment was conducted during a drought year in an arid grassland (226 mm annual rainfall), which might have been expected to be water-rather than nutrient-limited. Our results support the hypothesis that plant diversity may be maintained by high-dimensional tradeoffs among species in their abilities to compete for multiple limiting factors.     

DNA analyses support the hypothesis that infanticide is adaptive in langur monkeys.

Although the killing of dependent infants by adult males is a widespread phenomenon among primates, its causes and consequences still remain hotly debated. According to the sexual selection hypothesis, infanticidal males will gain a reproductive advantage provided that only unrelated infants are killed and that the males increase their chances of siring the next infants. Alternatively, the social pathology hypothesis interprets infanticide as a result of crowded living conditions and, thus, as not providing any advantage. Based on DNA analyses of wild Hanuman langurs (Presbytis entellus) we present the first evidence that male attackers were not related to their infant victims. Furthermore, in all cases the presumed killers were the likely fathers of the subsequent infants. Our data, therefore, strongly support the sexual selection hypothesis interpreting infanticide as an evolved, adaptive male reproductive tactic.