Lars Forsberg

Influence of genetic dissimilarity in the reproductive success and mate choice of brown trout – females fishing for optimal MHC dissimilarity

We examined the reproductive success of 48 adult brown trout (Salmo trutta L.) which were allowed to reproduce in a stream that was controlled for the absence of other trout. Parentage analyses based on 11 microsatellites permitted us to infer reproductive success and mate choice preferences in situ. We found that pairs with intermediate major histocompatibility complex (MHC) dissimilarity mated more often than expected by chance. It appears that female choice was the driving force behind this observation because, compared with other individuals, males with intermediate MHC dissimilarity produced a larger proportion of offspring, whereas female reproductive output did not show this pattern. Hence, rather than seeking mates with maximal MHC dissimilarity, as found in several species, brown trout seemed to prefer mates of intermediate MHC difference, thus supporting an optimality‐based model for MHC‐dependent mate choice.

Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer

Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive. From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17–3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56–8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.

Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells

Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

Smoking is associated with mosaic loss of chromosome Y

Men beware, when smoke gets in your Ys The relationship between tobacco smoking and elevated cancer risk has been recognized for 60 years. Yet what smoking does to our genetic material is still not fully understood. New work suggests that men should be particularly concerned. In a study of over 6000 men, Dumanski et al. find that men who smoke are more than three times as likely as nonsmokers to show loss of the Y chromosome in their blood cells. Whether this is a causal factor in cancer development or simply a marker of more consequential damage on other chromosomes could not be deduced from the study. Science, this issue p. 81 Men who smoke are over three times more likely than nonsmokers to show loss of the Y chromosome in their blood cells. Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared with females. This observation, together with the fact that males have a higher incidence of and mortality from most non–sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.8 to 6.7; Uppsala Longitudinal Study of Adult Men: OR = 2.4, 95% CI = 1.6 to 3.6; and Prospective Investigation of the Vasculature in Uppsala Seniors: OR = 3.5, 95% CI = 1.4 to 8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

Mosaicism in health and disease — clones picking up speed

Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.

Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime

The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders.

Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid

The mechanism behind Ca(2)(+) entry into the parathyroid cells has been widely debated, and the molecular identities of the responsible ion channels have not been established yet. In this study, we show that the parathyroid cells lack voltage-operated Ca(2)(+) channels. Passive store depletion by thapsigargin, on the other hand, induces a large non-voltage-activated non-selective cation current. The increase in intracellular Ca(2)(+) caused by thapsigargin is attenuated by 2-aminoethoxydiphenyl borate, a blocker of store-operated Ca(2)(+) entry (SOCE). Candidate molecules for non-voltage-operated Ca(2)(+) signaling were investigated. These included members of the transient receptor potential canonical (TRPC) ion channel family, as well as Ca(2)(+) release-activated Ca(2)(+) modulator 1 (Orai1) and stromal interaction molecule 1 (STIM1) that are key proteins in the SOCE pathway. Using RT-PCR screening, quantitative real-time PCR, and western blot, we showed expression of TRPC1, TRPC4, and TRPC6; Orai1; and STIM1 genes and proteins in normal and adenomatous human parathyroid tissues. Furthermore, co-immunoprecipitation experiments demonstrated a ternary complex of TRPC1-Orai1-STIM1, supporting a physical interaction between these molecules in human parathyroid.

Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16–21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

Somatic Mosaicism for Chromosome X and Y Aneuploidies in Monozygotic Twins Heterozygous for Sickle Cell Disease Mutation

Somatic genetic variation in health and disease is poorly explored. Monozygotic (MZ) twins are a suitable model for studies of somatic mosaicism since genetic differences in twins derived from the same zygote represent an irrefutable example of somatic variation. We report the analysis of a pair of generally healthy female MZ twins, discordant for somatic mosaicism for aneuploidy of chromosomes X and Y. Both twins are heterozygous carriers of sickle cell disease mutation. Genotyping of blood DNA from both twins using Illumina Human 610 SNP array revealed a copy number imbalance for chromosome X in a proportion of cells in one twin. Fluorescent in situ hybridization (FISH) analysis confirmed monosomy X (45,X) in 7% of proband nucleated blood cells. Unexpectedly, FISH analysis of cells from the other twin revealed 45,X and 46,XY lineages, both present in 1% of cells. The mechanism behind formation of these aneuploidies suggests several aberrant chromosome segregation events in meiosis and mitoses following conception. Our report contributes to the delineation of the frequency of somatic structural genomic variation in normal MZ twins. These results also illustrate the plasticity of the human genome for tolerating large copy number changes in healthy subjects and show the sensitivity of the Illumina platform for detection of aberrations that are present in a minority of the studied cells.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.