Genetik Ufku

How has our understanding of the brain evolved? And what can its progress tell us about the way science works? Armin Schneider explores these questions in his review of Charles Gross' new collection of essays on the history of neuroscience in Fire in the Quill.

The Robo3 receptor controls midline crossing by axons. Deleting Robo3 in specific commissural neurons with a conditional knockout reveals their contribution to sensory and motor integration, and models human neurological conditions.

Geneticists have long known that centromeres suppress crossing over, but considerable evidence indicates that they appear to recombine. Confirmation of gene conversion in maize centromeres explains this paradox.

Data from maize show that centromeres strongly suppress crossing over and instead undergo frequent genetic exchange in the form of gene conversion.

Upon DNA damage, a cytosolic form of the mitochondrial enzyme fumarase moves into the nucleus where, by virtue of its enzymatic activity, it participates in the cell's response to DNA damage. This potentially explains its known role as a tumor suppressor.

A surprising level of evolutionary plasticity is revealed by analysis of differences between related yeasts in the mechanisms regulating the essential cellular process of ribosomal gene expression.

A long-standing enigma in the fields of DNA repair and cancer chemotherapy is why it is that cells starved of the base thymine die rapidly. This process, called thymineless death (TLD), is conserved in bacterial, yeast, and human cells and is the mode of action of important cancer chemotherapeutic drugs. Tumors that become resistant to those drugs have ceased to die from TLD. Despite its ubiquity, importance, and having been studied for more than 50 years, the mechanism(s) of TLD remained elusive. Here we show that a large fraction of TLD requires RecA, the central protein in homologous recombinational (HR) DNA repair, and activation of the bacterial DNA–damage (or SOS) response, which RecA controls. We find that of the 40 or so proteins upregulated during an SOS response, SulA, an inhibitor of cell division, accounts for most of how SOS–activation causes TLD. In cells undergoing TLD, we observe blocked replication of the E. coli chromosome followed by loss of DNA near the replication origin then terminus. This implies that much of TLD results from an irreversible cell-cycle checkpoint that blocks cell division when single-stranded DNA (the SOS–inducing signal) accumulates and that the rest results from DNA destruction, models for which are presented.

Many association studies have been published looking for genetic variants contributing to a variety of human traits such as obesity, diabetes, and height. Because the frequency of genetic variants can differ across populations, it is important to have estimates of genetic ancestry in the individuals being studied. In this study, we were able to measure genetic ancestry in populations of mixed ancestry by genotyping pooled, rather than individual, DNA samples. This represents a rapid and inexpensive means for modeling genetic ancestry and thus could facilitate future association or population-genetic studies in populations of unknown ancestry for which whole-genome data do not already exist.

Our knowledge of the genetic basis of normal pigmentation variation in human populations is quite incomplete. Recent studies have identified some of the genes responsible for the reduction in melanin content in European populations, but this is not the case for other population groups, such as East Asians. Here, we report that a genetic variant located within the gene OCA2 (rs1800414) is associated with skin pigmentation in two samples of East Asian ancestry. The allele associated with lower melanin levels is found at high frequencies in East Asian populations, but is absent or at very low frequencies in other population groups. This is one of the first reports of association of genetic markers with quantitative measures of pigmentation in East Asian populations and it confirms previous evidence indicating that evolution towards light skin occurred, at least in part, independently in Europe and East Asia. The OCA2 gene has been under positive selection in Europe and East Asia, but different alleles have been selected in each region.

In contrast to animals, where germline differentiation initiates early in embryogenesis, germline differentiation in plants starts in the adult phase during reproductive development. Transpositions of transposable elements in both somatic and gametic cells can be transmitted to the next generation. As a result, plant genomes may contain transposable elements exhibiting a variety of tissue-specific activities. Thus far, the spatio-temporal activity of LTR retrotransposons, the most abundant class of transposable elements in plants, has not been well characterized. Here, we report a detailed analysis of the spatio-temporal transposition pattern of a plant LTR retrotransposon in the endogenous system. Using the model legume Lotus japonicus, we found that LORE1a, a member of the chromovirus LORE1 family that belongs to the Gypsy superfamily, was epigenetically de-repressed via tissue culture. Activation was stochastic and derepression was maintained in regenerated plants. This feature made it possible to trace the original spatio-temporal activity of the retrotransposon in the intact plants. We determined that the plant chromovirus retrotransposes mainly in the male germline, without obvious insertional preferences for chromosomal regions. This finding suggests that the tissue specificity of transposable elements should be taken into account when considering their impact on the host genome dynamics and evolution.

The regulation of gene activity by transcription factors is crucial to the function of all cells. Here, we studied the mechanisms of action of the largest family of gene regulators encoded by the human genome, the so-called KRAB–containing zinc finger proteins (KRAB–ZFPs), which in concert with their universal cofactor KAP1 act as transcriptional repressors. For this, we used two parallel approaches. First, by targeting an ectopic KRAB domain to hundreds of different genes, we found that KRAB/KAP1 can repress promoters located several tens of kilobases from the repressor DNA docking site. We further could show that KRAB induces such long-range effects by mediating the spread of repressive chromatin marks along the body of the gene, resulting in a block of transcriptional initiation at the promoter. In a second set of experiments, we analyzed an endogenous KRAB–ZFP gene cluster, where we could also document KAP1–dependent heterochromatin spreading and transcriptional repression. Together, these results support a model whereby KRAB–ZFPs and KAP1 can mediate long-range transcriptional repression through the spread of silencing chromatin marks. This study thus provides insight into KRAB/KAP1–induced gene regulation at KRAB–ZFP gene clusters, and will further help interpret genome-wide studies of KRAB–ZFPs and KAP1 DNA binding patterns.

Congenital ocular malformations affecting the optic nerve are an important cause of childhood blindness. The papillorenal syndrome (PRS) is an autosomal dominant disorder that causes congenital optic nerve and kidney abnormalities, which may result in legal blindness and renal failure, respectively. Many cases of PRS are caused by mutations in the paired-box transcription factor PAX2. In this paper, we describe a novel mouse model of this human disease caused by a missense mutation in the Pax2 gene at the same position of one of the few disease-causing missense mutations in humans. We characterize the ocular and non-ocular phenotypes of this mouse and model the effect that murine and human Pax2/PAX2 mutations have on protein structure. We also experimentally test the effect these missense mutations have on protein localization, transactivation, and DNA binding, concluding that all three reduce steady-state levels of protein in vitro and (in p.T74A) in vivo by reducing protein stability. This work will help us better understand the pathophysiology of PRS and to dissect the molecular interactions important in normal PAX2 function.

XPF-ERCC1 is a nuclease that plays a critical role in DNA repair. Mutations in XPF are linked to xeroderma pigmentosum, characterized by sun sensitivity, high incidence of skin cancer, and neurodegeneration, or XFE progeroid syndrome, a disease of accelerated aging. Herein we report the unexpected finding that mutations in XPF cause mislocalization of XPF-ERCC1 to the cytoplasm. Recombinant mutant XPF-ERCC1 derived from XP– and XFE–causing alleles are catalytically active and if delivered to the nucleus of cells restore DNA repair. This demonstrates that protein mislocalization contributes to defective DNA repair and disease arising as a consequence of mutations in XPF. It also illustrates a novel mechanism of regulating a cell's capacity for DNA repair: by manipulating nuclear localization of XPF-ERCC1 to enhance or inhibit repair and to prevent cancer or tumor resistance to chemotherapy, respectively.

In Drosophila the sex-specific ON/OFF regulation of Sex-lethal (Sxl) is controlled by an autoregulatory splicing mechanism that depends on the SXL protein interacting with general splicing factors. Here we identify PPS as a novel component of the machinery required for Sxl splicing autoregulation by showing that the lack of pps function interferes with Sxl expression and that the PPS protein is physically linked to the Sxl pre–mRNA, the SXL protein and components of the general splicing machinery. PPS, however, stands apart from all other proteins known to control Sxl splicing because it is not a general splicing factor. Furthermore, PPS has a distinct pattern of accumulation along the Sxl transcription unit that suggests PPS is loaded onto the RNA at the promoter. Together with the observation that the PPS protein contains four signature motifs typically found in proteins that function in transcriptional regulation, our data suggest that linking transcription to splicing regulation is important for controlling Sxl expression. This idea is especially intriguing because it indicates that the coupling of transcription and splicing seen in vitro and in cell culture studies is likely to be pertinent to developmentally controlled patterns of gene expression in the living animal.

In this essay, Abigail Shearin and Elaine Ostrander discuss the proposed genomic mechanisms for the extraordinary level of phenotypic variation observed in the domestic dog and the evidence detailing the variants responsible for the many shapes, sizes, textures, and colors of man's best friend.

It is easy to dismiss reconstructed organisms and behaviors from the past as “mere speculation”, but empirical evidence, comparison with modern analogs, and biomechanical modeling can provide remarkable insights.

A new snake from Upper Cretaceous rocks in India is found with hatchling sauropod dinosaurs, demonstrating that large, gape-limited snakes were probably capable of taking in moderate-sized vertebrate prey.

While disruption of p53 is selectively neutral within non-stressed hematopoiesis, it confers a strong selective advantage upon irradiation, leading to expansion of p53 mutant clones and lymphoma development.

In this essay, Abigail Shearin and Elaine Ostrander discuss the proposed genomic mechanisms for the extraordinary level of phenotypic variation observed in the domestic dog and the evidence detailing the variants responsible for the many shapes, sizes, textures, and colors of man's best friend.