Genetik Ufku

The diversity of wing patterns in Heliconius butterflies is a longstanding example of both Müllerian mimicry and adaptive radiation. The genetic regions controlling such patterns are “hotspots” for adaptive evolution, with small regions of the genome controlling major changes in wing pattern. Across multiple hybrid zones in Heliconius melpomene and related species, we no find no strong population signal of recent selection. Nonetheless, we find significant associations between genetic variation and wing pattern at multiple sites. This suggests patterning alleles are relatively old, and might be a better model for most natural adaptation, in contrast to the simple genetic basis of recent human-induced selection such as pesticide resistance. Strikingly, across the region controlling the red forewing band, a very strong association with phenotype implicates three genes as potentially being involved in control of wing pattern. One of these, a kinesin gene, shows parallel differences in expression levels between divergent forms in the two mimetic species, making it a strong candidate for control of wing pattern. These results show that mimicry involves parallel changes in gene expression and strongly suggest a role for this gene in control of wing pattern.

Identifying the genetic changes responsible for beneficial variation is essential for understanding how organisms adapt. Here, we use a combination of mapping, population genetic analysis, and gene expression studies to identify the genomic regions responsible for phenotypic evolution in the Neotropical butterfly Heliconius erato. H. erato, together with its co-mimic H. melpomene, have undergone parallel and concordant radiations in their warningly colored wing patterns across Central and South America. The “genes” underlying the H. erato color pattern radiation are classic examples of Mendelian loci of large effect and are under strong natural selection. Nonetheless, we do not see a clear molecular signal of recent natural selection, suggesting that the H. erato color pattern radiation, or the alleles that underlie it, may be quite old. Moreover, rather than being single locus, the genetic patterns suggest that multiple, widely dispersed loci may underlie pattern variation in H. erato. One of these loci, a kinesin gene, shows parallel expression differences between races during wing pattern formation in both H. erato and H. melpomene, suggesting that it plays an important role in pattern variation. High rates of recombination within naturally occurring H. erato hybrid zones mean that finer genetic dissection will allow us to localize causative sites and better understand the history and molecular basis of this extraordinary adaptive radiation.

The histiocytoses are a group of systemic disorders usually confined to childhood and are caused by an excessive number of histiocytes which phagocytose other cells and process antigens. Although nearly a century has passed since histiocytic disorders were recognised, their pathophysiology remains largely unclear, and treatment is nonspecific. The identification of SLC29A3 mutations as the molecular basis for a familial form of syndromic histiocytosis (FHC/RDD) confirms a direct link between Faisalabad histiocytosis and Rosai-Dorfman disease and links these disorders to other SLC29A3-associated phenotypes.

Here we address the issue of how genetic information is passed from one generation to the next without the involvement of specific DNA sequences. This type of inheritance is referred to as epigenetics. Centromeric sequences are highly variable and in many cases are not sufficient for centromere function. Rather, secondary features of the DNA, such as methylation or associated RNA molecules may serve to recruit key centromere binding proteins. Prior data from several species have established that single-stranded RNAs are surprisingly abundant on centromeric chromatin. Here we identified the DNA-binding domain of a key centromere binding protein in maize (CENPC) and showed that it requires single-stranded RNA to effectively bind DNA in vitro. When the DNA/RNA binding domain was deleted, the accuracy of CENPC targeting to centromeres was reduced but not abolished. The results bolster the view that centromere-bound RNA is one component of the epigenetic determination process that assures centromeres are stably inherited. In addition, our data suggest a general mechanism for how RNA can influence the binding of chromatin proteins to DNA.

Age-related macular degeneration (AMD) is the leading blindness cause in western countries. Several genes encoding components of the complement pathway—including CFH, C2/BF, and C3—have been confirmed to be associated with AMD, as well as a region on 10q26 that encompasses two genes. Recent data have suggested that loss of LOC387715 on 10q26, mediated by an insertion/deletion (in/del) at its 3'UTR that destabilizes its message, is causally related with the disorder. We found that a common disease haplotype including the in/del and rs11200638 also has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. We propose a binary model where downregulation of LOC387715 and concomitant upregulation of HTRA1 best explain the risk associated with the 10q26 AMD region.

Organisms can inherit information beyond DNA sequence, a phenomenon known as epigenetic inheritance. It is widely believed that chromatin marks provide a carrier for epigenetic information, a hypothesis that is less-supported than generally believed. In this study, we measure the erasure of a “memory” mark of active transcription, H3K4me3. We find that this signal-responsive chromatin mark largely returns to baseline levels within one generation. Furthermore, we find that this erasure occurs during S phase in a manner consistent with its loss during replication, yet we find that replication only contributes modestly to the erasure process. Instead, active enzymatic demethylation is required for erasure. Together, these results show that even chromatin states widely associated with epigenetic memory are only maintained in the ongoing presence of activating signals, and are not generally heritable.

Expansion of a stretch of glutamines near the amino-terminus of huntingtin (htt), the protein product of the IT15 gene, is a deleterious mutation that causes Huntington's disease (HD). Here we show, in contrast, that deletion of htt's normal polyglutamine stretch (ΔQ-htt) is a potentially beneficial mutation that can ameliorate HD mouse model phenotypes when ΔQ-htt is expressed together with a version of htt with the HD mutation. In addition, ΔQ-htt expression can enhance longevity when expressed in either an HD mouse model or in non–HD mice. ΔQ-htt's effects on both lifespan and HD model phenotypes are likely due to an increase in autophagy, a major recycling pathway in cells that is involved in the turnover of cellular components, and aggregated protein. Based on our results, we suggest that development of therapeutic agents that can stimulate autophagy may help both in treating neurodegenerative disorders like HD and also in increasing longevity.

ATM and ATR kinases are two evolutionarily conserved sensors of DNA damage, responsible for maintaining stable genomes in all eukaryotic cells. These two kinases safeguard eukaryotic genomes against undesired double-stranded DNA breaks (DSBs) and errors during duplication of genomic DNA. Furthermore, ATM and ATR are redundantly required for stable maintenance of telomeres, protective structures at ends of linear eukaryotic chromosomes. Our current study in fission yeast demonstrates that the previously defined C-terminal Tel1ATM interaction domain of the DNA repair protein Nbs1, which contributes to recruitment of Tel1ATM to DSBs, is dispensable for recruitment of Tel1ATM to telomeres, due to a previously unrecognized kinase-independent role of ATR in recruitment of Tel1ATM to telomeres. Furthermore, the N-terminus of Nbs1 was found to be critical for recruitment of both ATR and ATM to telomeres. Regulators of telomere maintenance have recently emerged as potentially important therapeutic targets against tumorigenesis and aging in mammalian cells. Since proteins responsible for proper maintenance of telomeres and cellular responses to DNA damage are highly conserved between fission yeast and mammalian cells, a newly uncovered molecular crosstalk between ATM and ATR might also play critical roles in telomere maintenance and DNA damage responses in mammalian cells.

An advantageous mutation spreads from generation to generation in a population until individuals that carry it, because of their higher reproductive success, completely replace those that do not. This process, commonly known as positive Darwinian selection, requires the selected mutation to induce a new non-neutral heritable phenotypic trait, and this has been shown to occur unexpectedly frequently during recent human evolution. Although the exact advantageous mutation is difficult to identify, it leaves a wider footprint on neighbouring linked neutral variation called a selective sweep. We have developed an empirical method that uses whole-genome shotgun sequences of single individuals to detect selective sweeps. By doing so, we were able to extend to chimpanzee, orangutan, and macaque individuals analyses of recent positive selection that until now were only available for human. Comparisons of genes candidates for positive selection between human and non-human primates then revealed an unexpectedly high number of cases where a selective sweep at a gene in humans is mirrored by independent positive selection at the same gene in multiple other primates. This result has future implications for understanding the nature of biological changes that underlie selective sweeps in humans.

In this issue of PLoS Genetics, Wang et al. report a spontaneous pseudoviviparous mutant phoenix (pho) in rice. In pho plants, all spikelets are replaced by young plantlets, and the reproductive strategy is completely changed from sexual to asexual. Further analyses revealed that pho is caused by mutations of two MADS-box transcription factors. These findings provide an insight into the mechanism of pseudovivipary in plants.

Image Credit: Zhukuan Cheng (Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, China)

In eukaryotes genetic crossovers are responsible for generating genetic diversity and ensuring the proper segregation of chromosomes. Genetic crossovers are tightly clustered in hotspots. Although the existence of hotspots in humans is clearly proven, mechanisms of their formation and the regulation of meiotic recombination in general remain poorly understood. An additional complication in studies of meiotic recombination is the fact that the direct experimental mapping of human hotspots on a genome-wide scale is not feasible with current methods. The best available indirect methods compute the position of hotspots from patterns of historic associations between genetic markers in population samples. In this study we determined the positions of genetic crossovers in ten pedigrees of European origin and then compared the positions of crossovers with the hotspots computed from HapMap data. Importantly, we find that the population-averaged computed map is in close agreement with the observed distribution of genetic crossovers. We also find that cryptic hotspots that are not easily detected in the computed European map can be more effectively identified if other populations are included in the analysis. Our analysis shows that high-resolution recombination profiles are highly similar between distantly related populations and that by including computed hotspots from several populations we can predict nearly all crossovers.

Glioblastoma has a particularly dismal prognosis with median survival time of less than fifteen months. Here, we describe the broad genome sequencing of U87MG, a commonly used and thus well-studied glioblastoma cell line. One of the major features of the U87MG genome is the large number of chromosomal abnormalities, which can be typical of cancer cell lines and primary cancers. The systematic, thorough, and accurate mutational analysis of the U87MG genome comprehensively identifies different classes of genetic mutations including single-nucleotide variations (SNVs), insertions/deletions (indels), and translocations. We found 2,384,470 SNVs, 191,743 small indels, and 1,314 large structural variations. Known gene models were used to predict the effect of these mutations on protein-coding sequence. Mutational analysis revealed 512 genes homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and up to 35 by interchromosomal translocations. The major mutational mechanisms in this brain cancer cell line are small indels and large structural variations. The genomic landscape of U87MG is revealed to be much more complex than previously thought based on lower resolution techniques. This mutational analysis serves as a resource for past and future studies on U87MG, informing them with a thorough description of its mutational state.