The question of the relative evolutionary roles of adaptive and nonadaptive processes has been a central debate in population genetics for nearly a century. While advances have been made in the theoretical development of the underlying models, and statistical methods for estimating their parameters from large-scale genomic data, a framework for an appropriate null model remains elusive. A model incorporating evolutionary processes known to be in constant operation, genetic drift (as modulated by the demographic history of the population) and purifying selection, is lacking. Without such a null model, the role of adaptive processes in shaping within- and between-population variation may not be accurately assessed. Here, we investigate how population size changes and the strength of purifying selection affect patterns of variation at "neutral" sites near functional genomic components. We propose a novel statistical framework for jointly inferring the contribution of the relevant selective and demographic parameters. By means of extensive performance analyses, we quantify the utility of the approach, identify the most important statistics for parameter estimation, and compare the results with existing methods. Finally, we reanalyze genome-wide population-level data from a Zambian population of Drosophila melanogaster, and find that it has experienced a much slower rate of population growth than was inferred when the effects of purifying selection were neglected. Our approach represents an appropriate null model, against which the effects of positive selection can be assessed.

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.

The prospect of the 2019-20 season being declared 'null and void' looms large over football. We take a look at some of the records, achievements and landmarks that could be erased from history.

Cronulla captain Wade Graham has called out anti-vaxxers who refuse to get a flu shot, saying they should put their teammates above their own personal...

The Prime Minister's favourite team will begin their 2020 campaign against the South Sydney Rabbitohs - supported by opposition leader Anthony Albanese - at ANZ Stadium in Sydney.

Two players from the Cronulla Sharks have been sent home from team training after falling ill with flu-like symptoms.

Mr Morrison announced the government would ban 'non essential' public gatherings of more than 500 people in Australia from Monday.

The life-long Sharks fan had just hours before insisted he would attend his team's first NRL game of the season against the South Sydney Rabbitohs.

Kylie Jenner is attempting to nullify a trademark held by a company who copyrighted the name 'Stormi Couture' just after her daughter Stormi Webster by Travis Scott was born.

The prospect of the 2019-20 season being declared 'null and void' looms large over football. We take a look at some of the records, achievements and landmarks that could be erased from history.

WILL KELLEHER AND NIK SIMON AT THE YOKOHAMA STADIUM: South Africa edged a battling Wales in a tight World Cup semi-final on Sunday to book their spot in the tournament decider.

India has been in a state of dejection and self-denial over Kashmir since Independence.

Paris : Atlantis Press : Imprint: Atlantis Press, 2014