Molecular evolution of FOXP2, a gene involved in speech and language

Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution.     

Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling

The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues.     

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.     

Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.     

Hormone content of mouse pancreatic islets subjected to different in vivo and in vitro functional demands

Summary Mice treated for 4 days with tolbutamide displayed decreased serum glucose values with a concomitant decrease of their islet insulin content. Mouse islets cultured for 1 week at a low (3 mM) or a high (28 mM) glucose concentration contained less insulin than non-cultured islets and islets cultured at a medium (11 mM) glucose concentration. All groups of cultured islets contained more glucagon than non-cultured islets. The somatostatin content of high- and medium-glucose cultured islets was higher than that of freshly isolated islets.The skilled technical assistance of Astrid Nordin, Ewa Forsbeck and Eva Törnelius is gratefully acknowledged. Financial support was received from the Swedish Medical Research Council (12X-109; 12X-2297), the Nordic Insulin Fund and the Swedish Diabetes Association.     

Contrasting patterns of early twenty-first-century glacier mass change in the Himalayas

Glaciers are among the best indicators of terrestrial climate variability, contribute importantly to water resources in many mountainous regions and are a major contributor to global sea level rise. In the Hindu Kush-Karakoram-Himalaya region (HKKH), a paucity of appropriate glacier data has prevented a comprehensive assessment of current regional mass balance. There is, however, indirect evidence of a complex pattern of glacial responses in reaction to heterogeneous climate change signals. Here we use satellite laser altimetry and a global elevation model to show widespread glacier wastage in the eastern, central and south-western parts of the HKKH during 2003-08. Maximal regional thinning rates were 0.66?±?0.09 metres per year in the Jammu-Kashmir region. Conversely, in the Karakoram, glaciers thinned only slightly by a few centimetres per year. Contrary to expectations, regionally averaged thinning rates under debris-mantled ice were similar to those of clean ice despite insulation by debris covers. The 2003-08 specific mass balance for our entire HKKH study region was -0.21?±?0.05?m?yr(-1) water equivalent, significantly less negative than the estimated global average for glaciers and ice caps. This difference is mainly an effect of the balanced glacier mass budget in the Karakoram. The HKKH sea level contribution amounts to one per cent of the present-day sea level rise. Our 2003-08 mass budget of -12.8?±?3.5 gigatonnes (Gt) per year is more negative than recent satellite-gravimetry-based estimates of -5?±?3?Gt?yr(-1) over 2003-10 (ref. 12). For the mountain catchments of the Indus and Ganges basins, the glacier imbalance contributed about 3.5% and about 2.0%, respectively, to the annual average river discharge, and up to 10% for the Upper Indus basin.     

Great ape DNA sequences reveal a reduced diversity and an expansion in humans

The extent of DNA sequence variation of chimpanzees is several-fold greater than that of humans. It is unclear, however, if humans or chimpanzees are exceptional among primates in having low and high amounts of DNA sequence diversity, respectively. To address this, we have determined approximately 10,000 bp of noncoding DNA sequences at Xq13.3 (which has been extensively studied in both humans and chimpanzees) from 10 western lowland gorillas (Gorilla gorilla gorilla) and 1 mountain gorilla (Gorilla gorilla beringei; that is, from 2 of the 3 currently recognized gorilla subspecies), as well as 8 Bornean (Pongo pygmaeus pygmaeus) and 6 Sumatran (Pongo pygmaeus abelii) orang-utans, representing both currently recognized orang-utan subspecies. We show that humans differ from the great apes in having a low level of genetic variation and a signal of population expansion.     

Neanderthals in central Asia and Siberia

Morphological traits typical of Neanderthals began to appear in European hominids at least 400,000 years ago and about 150,000 years ago in western Asia. After their initial appearance, such traits increased in frequency and the extent to which they are expressed until they disappeared shortly after 30,000 years ago. However, because most fossil hominid remains are fragmentary, it can be difficult or impossible to determine unambiguously whether a fossil is of Neanderthal origin. This limits the ability to determine when and where Neanderthals lived. To determine how far to the east Neanderthals ranged, we determined mitochondrial DNA (mtDNA) sequences from hominid remains found in Uzbekistan and in the Altai region of southern Siberia. Here we show that the DNA sequences from these fossils fall within the European Neanderthal mtDNA variation. Thus, the geographic range of Neanderthals is likely to have extended at least 2,000 km further to the east than commonly assumed.