Arcadi Navarro

Comparative and demographic analysis of orang-utan genomes

‘Orang-utan’ is derived from a Malay term meaning ‘man of the forest’ and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (Ne) expanded exponentially relative to the ancestral Ne after the split, while Bornean Ne declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.

Great ape genetic diversity and population history

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria–Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

ACCUMULATING POSTZYGOTIC ISOLATION GENES IN PARAPATRY: A NEW TWIST ON CHROMOSOMAL SPECIATION

Abstract Chromosomal rearrangements can promote reproductive isolation by reducing recombination along a large section of the genome. We model the effects of the genetic barrier to gene flow caused by a chromosomal rearrangement on the rate of accumulation of postzygotic isolation genes in parapatry. We find that, if reproductive isolation is produced by the accumulation in parapatry of sets of alleles compatible within but incompatible across species, chromosomal rearrangements are far more likely to favor it than classical genetic barriers without chromosomal changes. New evidence of the role of chromosomal rearrangements in parapatric speciation suggests that postzygotic isolation is often due to the accumulation of such incompatibilities. The model makes testable qualitative predictions about the genetic signature of speciation.

The genome of melon (Cucumis melo L.)

We report the genome sequence of melon, an important horticultural crop worldwide. We assembled 375 Mb of the double-haploid line DHL92, representing 83.3% of the estimated melon genome. We predicted 27,427 protein-coding genes, which we analyzed by reconstructing 22,218 phylogenetic trees, allowing mapping of the orthology and paralogy relationships of sequenced plant genomes. We observed the absence of recent whole-genome duplications in the melon lineage since the ancient eudicot triplication, and our data suggest that transposon amplification may in part explain the increased size of the melon genome compared with the close relative cucumber. A low number of nucleotide-binding site–leucine-rich repeat disease resistance genes were annotated, suggesting the existence of specific defense mechanisms in this species. The DHL92 genome was compared with that of its parental lines allowing the quantification of sequence variability in the species. The use of the genome sequence in future investigations will facilitate the understanding of evolution of cucurbits and the improvement of breeding strategies.

Chromosomal speciation revisited: rearranging theory with pieces of evidence.

The suggestion that chromosomal rearrangements play a role in speciation resulted from the observation that heterokaryotypes are often infertile. However, the first chromosomal speciation models were unsatisfactory and data available to test them was scarce. Recently, large amounts of data have become available and new theoretical models have been developed explaining how rearrangements facilitate speciation in the face of gene flow. Here, we re-examine theoretical predictions and revisit different sources of data. Although rearrangements are often associated with increased levels of divergence, unequivocal demonstration that their role in suppressing recombination results in speciation is often lacking. Finally, we question some previous predictions and suggest new empirical and theoretical approaches to understanding the relevance of rearrangements in the origin of species.

Statistical Power Analysis of Neutrality Tests Under Demographic Expansions, Contractions and Bottlenecks With Recombination

Several tests have been proposed to detect departures of nucleotide variability patterns from neutral expectations. However, very different kinds of evolutionary processes, such as selective events or demographic changes, can produce similar deviations from these tests, thus making interpretation difficult when a significant departure of neutrality is detected. Here we study the effects of demography and recombination upon neutrality tests by analyzing their power under sudden population expansions, sudden contractions, and bottlenecks. We evaluate tests based on the frequency spectrum of mutations and the distribution of haplotypes and explore the consequences of using incorrect estimates of the rates of recombination when testing for neutrality. We show that tests that rely on haplotype frequencies—especially Fs and ZnS, which are based, respectively, on the number of different haplotypes and on the r2 values between all pairs of polymorphic sites—are the most powerful for detecting expansions on nonrecombining genomic regions. Nevertheless, they are strongly affected by misestimations of recombination, so they should not be used when recombination levels are unknown. Instead, class I tests, particularly Tajimas D or R2, are recommended.

A burst of segmental duplications in the genome of the African great ape ancestor

It is generally accepted that the extent of phenotypic change between human and great apes is dissonant with the rate of molecular change. Between these two groups, proteins are virtually identical, cytogenetically there are few rearrangements that distinguish ape–human chromosomes, and rates of single-base-pair change and retrotransposon activity have slowed particularly within hominid lineages when compared to rodents or monkeys. Studies of gene family evolution indicate that gene loss and gain are enriched within the primate lineage. Here, we perform a systematic analysis of duplication content of four primate genomes (macaque, orang-utan, chimpanzee and human) in an effort to understand the pattern and rates of genomic duplication during hominid evolution. We find that the ancestral branch leading to human and African great apes shows the most significant increase in duplication activity both in terms of base pairs and in terms of events. This duplication acceleration within the ancestral species is significant when compared to lineage-specific rate estimates even after accounting for copy-number polymorphism and homoplasy. We discover striking examples of recurrent and independent gene-containing duplications within the gorilla and chimpanzee that are absent in the human lineage. Our results suggest that the evolutionary properties of copy-number mutation differ significantly from other forms of genetic mutation and, in contrast to the hominid slowdown of single-base-pair mutations, there has been a genomic burst of duplication activity at this period during human evolution.

Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European

Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer.

Balancing Selection Is the Main Force Shaping the Evolution of Innate Immunity Genes

The evolutionarily recent geographic expansion of humans, and the even more recent development of large, relatively dense human settlements, has exposed our species to new pathogenic environments. Potentially lethal pathogens are likely to have exerted important selective pressures on our genome, so immunity genes can be expected to show molecular signatures of the adaptation of human populations to these recent conditions. While genes related to the acquired immunity system have indeed been reported to show traces of local adaptation, little is known about the response of the innate immunity system. In this study, we analyze the variability patterns in different human populations of fifteen genes related to innate immunity. We have used both single nucleotide polymorphism and sequence data, and through the analysis of interpopulation differentiation, the linkage disequilibrium pattern, and intrapopulation diversity, we have discovered some signatures of positive and especially balancing selection in these genes, thus confirming the importance of the immune system genetic plasticity in the evolutionary adaptive process. Interestingly, the strongest evidence is found in three TLR genes and CD14. These innate immunity genes play a pivotal role, being involved in the primary recognition of pathogens. In general, more evidences of selection appear in the European populations, in some case possibly related to severe population specific pressures. However, we also describe evidence from African populations, which may reflect parallel or long-term selective forces acting in different geographic areas.

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.