Evolution of dosage compensation

In polytene chromosome squashes from the fruit flyDrosophila melanogaster, the single, dosage-compensated X chromosome in males can be distinguished from the autosomes by the presence of an isoform of histone H4 acetylated at lysine 16, H4.Ac16. We have used H4.Ac16 as a marker to examine the evolving relationship between dosage compensation and sex chromosome composition in species ofDrosophila with one (D. melanogaster), two (D. pseudoobscura) or three (D. miranda) identifiable X chromosome arms. In each case, we find that H4.Ac16 is distributed as discrete, closely spaced bands along the entire length of each X chromosome, the only exception being the X2 chromosome ofD. miranda in which a terminal region constituting about 10% of the chromosome by length is not labelled with anti-H4.Ac16 antibodies. We conclude that, with this exception, dosage compensation extends along the X chromosomes of all three species. AsD. pseudoobscura andD. miranda diverged only about 2 Mya, the spread of dosage-compensated loci along X2 has been rapid, suggesting that regional changes rather than piecemeal, gene-by-gene, changes may have been involved.accepted for publication by H. C. Macgregor     

Drosophila UNR is required for translational repression of male-specific lethal 2 mRNA during regulation of X-chromosome dosage compensation

The inhibition of male-specific lethal 2 (msl-2) mRNA translation by the RNA-binding protein sex-lethal (SXL) is an essential regulatory step for X-chromosome dosage compensation in Drosophila melanogaster. The mammalian upstream of N-ras (UNR) protein has been implicated in the regulation of mRNA stability and internal ribosome entry site (IRES)-dependent mRNA translation. Here we have identified the Drosophila homolog of mammalian UNR as a cofactor required for SXL-mediated repression of msl-2 translation. UNR interacts with SXL, a female-specific protein. Although UNR is present in both male and female flies, binding of SXL to uridine-rich sequences in the 3' untranslated region (UTR) of msl-2 mRNA recruits UNR to adjacent regulatory sequences, thereby conferring a sex-specific function to UNR. These data identify a novel regulator of dosage compensation in Drosophila that acts coordinately with SXL in translational control.     

Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping

The identity and developmental potential of a human cell is specified by its epigenome that is largely defined by patterns of chromatin modifications including histone acetylation. Here we report high-resolution genome-wide mapping of diacetylation of histone H3 at Lys 9 and Lys 14 in resting and activated human T cells by genome-wide mapping technique (GMAT). Our data show that high levels of the H3 acetylation are detected in gene-rich regions. The chromatin accessibility and gene expression of a genetic domain is correlated with hyperacetylation of promoters and other regulatory elements but not with generally elevated acetylation of the entire domain. Islands of acetylation are identified in the intergenic and transcribed regions. The locations of the 46,813 acetylation islands identified in this study are significantly correlated with conserved noncoding sequences (CNSs) and many of them are colocalized with known regulatory elements in T cells. TCR signaling induces 4045 new acetylation loci that may mediate the global chromatin remodeling and gene activation. We propose that the acetylation islands are epigenetic marks that allow prediction of functional regulatory elements.     

Changes in lymphocyte chromatin in Down's syndrome revealed by the thermal denaturation method

A luminescence-microscopic study using acridine orange with a short-term culture of human cells showed that DNA melting profiles of the chromatin of intact lymphocytes of healthy donors are curves with maxima (F 530) in the temperature regions of 45, 65, 78, 85, 88, and 92°C (P<0.01). The melting profiles of lymphocytes of patients with Down's syndrome are curves with maxima in the temperature regions of 65, 85, 88, and 92°C (P<0.01). The absence of a decrease in the intensity of fluorescence between 78 and 85°C is evidently due to the greater degree of condensation of certain regions of the chromatin complex of the trisomic cells. The possible mechanisms of the structural changes in the interphase chromatin, of human lymphocytes under the influence of temperature are discussed.Institute of Medical Genetics, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Yudaev.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 6, pp. 672–674, June, 1976.     

Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison

Non-coding DNA comprises approximately 80% of the euchromatic portion of the Drosophila melanogaster genome. Non-coding sequences are known to contain functionally important elements controlling gene expression, but the proportion of sites that are selectively constrained is still largely unknown. We have compared the complete D. melanogaster and Drosophila simulans genome sequences to estimate mean selective constraint (the fraction of mutations that are eliminated by selection) in coding and non-coding DNA by standardizing to substitution rates in putatively unconstrained sequences. We show that constraint is positively correlated with intronic and intergenic sequence length and is generally remarkably strong in non-coding DNA, implying that more than half of all point mutations in the Drosophila genome are deleterious. This fraction is also likely to be an underestimate if many substitutions in non-coding DNA are adaptively driven to fixation. We also show that substitutions in long introns and intergenic sequences are clustered, such that there is an excess of substitutions <8 bp apart and a deficit farther apart. These results suggest that there are blocks of constrained nucleotides, presumably involved in gene expression control, that are concentrated in long non-coding sequences. Furthermore, we infer that there is more than three times as much functional non-coding DNA as protein-coding DNA in the Drosophila genome. Most deleterious mutations therefore occur in non-coding DNA, and these may make an important contribution to a wide variety of evolutionary processes.     

Language and the aging brain: patterns of neural compensation revealed by functional brain imaging

Human aging brings with it declines in sensory function, both in vision and in hearing, as well as a general slowing in a variety of perceptual and cognitive operations. Yet in spite of these declines, language comprehension typically remains well preserved in normal aging. We review data from functional magnetic resonance imaging (fMRI) to describe a two-component model of sentence comprehension: a core sentence-processing area located in the perisylvian region of the left cerebral hemisphere and an associated network of brain regions that support the working memory and other resources needed for comprehension of long or syntactically complex sentences. We use this two-component model to describe the nature of compensatory recruitment of novel brain regions observed when healthy older adults show the same success at comprehending sentences as their younger adult counterparts. We suggest that this plasticity in neural recruitment contributes to the stability of language comprehension in the aging brain.