Human evolutionary scholars have long supposed that the earliest stone tools were made by the genus Homo and that this technological development was directly linked to climate change and the spread of savannah grasslands. New fieldwork in West Turkana, Kenya, has identified evidence of much earlier hominin technological behaviour. We report the discovery of Lomekwi 3, a 3.3-million-year-old archaeological site where in situ stone artefacts occur in spatiotemporal association with Pliocene hominin fossils in a wooded palaeoenvironment. The Lomekwi 3 knappers, with a developing understanding of stone's fracture properties, combined core reduction with battering activities. Given the implications of the Lomekwi 3 assemblage for models aiming to converge environmental change, hominin evolution and technological origins, we propose for it the name 'Lomekwian', which predates the Oldowan by 700,000 years and marks a new beginning to the known archaeological record.

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Epigenetic silencing of MLH1 is the most common cause of defective DNA mismatch repair in endometrial and colorectal cancers. We hypothesized that variation in the MLH1 gene might contribute to the risk for MLH1 methylation and epigenetic silencing. We undertook a case-control study to test for the association between MLH1 variants and abnormal MLH1 methylation. Eight MLH1 SNPs were typed in the normal DNA from women with endometrial carcinoma. For these studies, the cases were women whose cancers exhibited MLH1 methylation (N 5 98) and the controls were women whose cancers had no MLH1 methylation (N 5 219). One MLH1 SNP, rs1800734, located in the MLH1 CpG island at 293 from the translation start site, was significantly associated with MLH1 methylation as were age at diagnosis and patient body mass index. In validation experiments, a similar-sized cohort of colorectal carcinoma patients (N 5 387) showed a similar degree of association with the 293 SNP; a smaller cohort of endometrial carcinomas (N 5 181) showed no association. Combining all 3 cohorts showed an odds ratio of 1.61 (95% CI: 1.20-2.16) for the AA or AG vs. GG genotype at the 293 SNP. Identification of risk alleles for MLH1 methylation could shed light on mechanisms of epigenetic silencing and may ultimately lead to new approaches to the prevention or treatment of malignancies associated with MLH1 inactivation. Epigenetic silencing of MLH1 is the most common cause of defective DNA mismatch repair. [2][3][4][5][6][7][8] In our large series of endometrial carcinomas, >20% have MLH1 promoter methylation.1 We previously showed that MLH1 methylation is associated with increased age at diagnosis.1 Furthermore, MSI1 endometrial cancers appear to be associated with lower body mass index (BMI).9 As is the case for endometrial cancers, MSI with MLH1 methylation is associated with older age at diagnosis in colorectal cancers. 6,10 MSI1 colorectal cancers tend to be right-sided tumors.11 To date, there have been no genetic factors associated with the risk for epigenetic silencing of MLH1 in tumors.Murrell et al. reported an association between polymorphisms in the IGF2 gene and Beckwith-Wiedemann syndrome, an overgrowth syndrome in which loss of imprinting of IGF2 and KCNQ1 is frequently observed.12 Variants in the IGF2 differentially methylated region were found to be significantly associated with sporadic Beckwith-Wiedemann syndrome in which loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 in the KCNQ1 gene was observed.12 This was the first evidence that sequence variation within a gene may be causally associated with abnormalities in methylation (loss of methylation).Unlike the loss of methylation in Beckwith-Wiedemann syndrome, the MLH1 methylation defect in endometrial cancer is a gain of methylation in sequences that are normally unmethylated. We hypothesized that germline variation in the MLH1 locus might contribute to the risk for MLH1 methylation. We undertook a case-control association study to test for MLH1...