Evolution of the human ASPM gene, a major determinant of brain size

The size of human brain tripled over a period of approximately 2 million years (MY) that ended 0.2-0.4 MY ago. This evolutionary expansion is believed to be important to the emergence of human language and other high-order cognitive functions, yet its genetic basis remains unknown. An evolutionary analysis of genes controlling brain development may shed light on it. ASPM (abnormal spindle-like microcephaly associated) is one of such genes, as nonsense mutations lead to primary microcephaly, a human disease characterized by a 70% reduction in brain size. Here I provide evidence suggesting that human ASPM went through an episode of accelerated sequence evolution by positive Darwinian selection after the split of humans and chimpanzees but before the separation of modern non-Africans from Africans. Because positive selection acts on a gene only when the gene function is altered and the organismal fitness is increased, my results suggest that adaptive functional modifications occurred in human ASPM and that it may be a major genetic component underlying the evolution of the human brain.     

Positive selection at the ASPM gene coincides with brain size enlargements in cetaceans

The enlargement of cetacean brain size represents an enigmatic event in mammalian evolution, yet its genetic basis remains poorly explored. One candidate gene associated with brain size evolution is the abnormal spindle-like microcephaly associated (ASPM), as mutations in this gene cause severe reductions in the cortical size of humans. Here, we investigated the ASPM gene in representative cetacean lineages and previously published sequences from other mammals to test whether the expansion of the cetacean brain matched adaptive ASPM evolution patterns. Our analyses yielded significant evidence of positive selection on the ASPM gene during cetacean evolution, especially for the Odontoceti and Delphinoidea lineages. These molecular patterns were associated with two major events of relative brain size enlargement in odontocetes and delphinoids. It is of particular interest to find that positive selection was restricted to cetaceans and primates, two distant lineages both characterized by a massive expansion of brain size. This result is suggestive of convergent molecular evolution, although no site-specific convergence at the amino acid level was found.     

A novel domain suggests a ciliary function for ASPM, a brain size determining gene

The N-terminal domain of abnormal spindle-like microcephaly-associated protein (ASPM) is identified as a member of a novel family of ASH (ASPM, SPD-2, Hydin) domains. These domains are present in proteins associated with cilia, flagella, the centrosome and the Golgi complex, and in Hydin and OCRL whose deficiencies are associated with hydrocephalus and Lowe oculocerebrorenal syndrome, respectively. Genes encoding ASH domains thus represent good candidates for primary ciliary dyskinesias. ASPM has been proposed to function in neurogenesis and to be a major determinant of cerebral cortical size in humans. Support for this hypothesis stems from associations between mutations in ASPM and primary microcephaly, and from the rapid evolution of ASPM during recent hominid evolution. The identification of the ASH domain family instead indicates possible roles for ASPM in sperm flagellar or in ependymal cells' cilia. ASPM's rapid evolution may thus reflect selective pressures on ciliary function, rather than pressures on mitosis during neurogenesis.     

Accelerated evolution of the pituitary adenylate cyclase-activating polypeptide precursor gene during human origin

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide abundantly expressed in the central nervous system and involved in regulating neurogenesis and neuronal signal transduction. The amino acid sequence of PACAP is extremely conserved across vertebrate species, indicating a strong functional constraint during the course of evolution. However, through comparative sequence analysis, we demonstrated that the PACAP precursor gene underwent an accelerated evolution in the human lineage since the divergence from chimpanzees, and the amino acid substitution rate in humans is at least seven times faster than that in other mammal species resulting from strong Darwinian positive selection. Eleven human-specific amino acid changes were identified in the PACAP precursors, which are conserved from murine to African apes. Protein structural analysis suggested that a putative novel neuropeptide might have originated during human evolution and functioned in the human brain. Our data suggested that the PACAP precursor gene underwent adaptive changes during human origin and may have contributed to the formation of human cognition.     

Evolution of ASPM is associated with both increases and decreases in brain size in primates

A fundamental trend during primate evolution has been the expansion of brain size. However, this trend was reversed in the Callitrichidae (marmosets and tamarins), which have secondarily evolved smaller brains associated with a reduction in body size. The recent pursuit of the genetic basis of brain size evolution has largely focused on episodes of brain expansion, but new insights may be gained by investigating episodes of brain size reduction. Previous results suggest two genes (ASPM and CDK5RAP2) associated with microcephaly, a human neurodevelopmental disorder, may have an evolutionary function in primate brain expansion. Here we use new sequences encoding key functional domains from 12 species of callitrichids to show that positive selection has acted on ASPM across callitrichid evolution and the rate of ASPM evolution is significantly negatively correlated with callitrichid brain size, whereas the evolution of CDK5RAP2 shows no correlation with brain size. Our findings strongly suggest that ASPM has a previously unsuspected role in the evolution of small brains in primates. ASPM is therefore intimately linked to both evolutionary increases and decreases in brain size in anthropoids and is a key target for natural selection acting on brain size.     

Metabolic costs of brain size evolution

In the ongoing discussion about brain evolution in vertebrates, the main interest has shifted from theories focusing on energy balance to theories proposing social or ecological benefits of enhanced intellect. With the availability of a wealth of new data on basal metabolic rate (BMR) and brain size and with the aid of reliable techniques of comparative analysis, we are able to show that in fact energetics is an issue in the maintenance of a relatively large brain, and that brain size is positively correlated with the BMR in mammals, controlling for body size effects. We conclude that attempts to explain brain size variation in different taxa must consider the ability to sustain the energy costs alongside cognitive benefits.     

Plausible mechanisms for brain structural and size changes in human evolution

Encephalization has many contexts and implications. On one hand, it is concerned with the transformation of eating habits, social relationships and communication, cognitive skills and the mind. Along with the increase in brain size on the other hand, encephalization is connected with the creation of more complex brain structures, namely in the cerebral cortex. It is imperative to inquire into the mechanisms which are linked with brain growth and to find out which of these mechanisms allow it and determine it. There exist a number of theories for understanding human brain evolution which originate from neurological sciences. These theories are the concept of radial units, minicolumns, mirror neurons, and neurocognitive networks. Over the course of evolution, it is evident that a whole range of changes have taken place in regards to heredity. These changes include new mutations of genes in the microcephalin complex, gene duplications, gene co-expression, and genomic imprinting. This complex study of the growth and reorganization of the brain and the functioning of hereditary factors and their external influences creates an opportunity to consider the implications of cultural evolution and cognitive faculties.     

Accelerated rates of floral evolution at the upper size limit for flowers

Evolutionary theory explains phenotypic change as the result of natural selection, with constraint limiting the direction, magnitude, and rate of response [1]. Constraint is particularly likely to govern evolutionary change when a trait is at perceived upper or lower limits. Macroevolutionary rates of floral-size change are unknown for any angiosperm family, but it is predicted that rates should be diminished near the upper size limit of flowers, as has been shown for mammal body mass [2]. Our molecular results show that rates of floral-size evolution have been extremely rapid in the endoholoparasite Rafflesia, which contains the world's largest flowers [3]. These data provide the first estimates of macroevolutionary rates of floral-size change and indicate that in this lineage, floral diameter increased by an average of 20 cm (and up to 90 cm)/million years. In contrast to our expectations, it appears that the magnitude and rate of floral-size increase is greater for lineages with larger flowered ancestors. This study suggests that constraints on rates of floral-size evolution may not be limiting in Rafflesia, reinforcing results of artificial- and natural-selection studies in other plants that demonstrated the potential for rapid size changes [4-6].     

Species-specific size expansion and molecular evolution of the oleosins in angiosperms

Oleosins are hydrophobic plant proteins thought to be important for the formation of oil bodies, which supply energy for seed germination and subsequent seedling growth. To better understand the evolutionary history and diversity of the oleosin gene family in plants, especially angiosperms, we systematically investigated the molecular evolution of this family using eight representative angiosperm species. A total of 73 oleosin members were identified, with six members in each of four monocot species and a greater but variable number in the four eudicots. A phylogenetic analysis revealed that the angiosperm oleosin genes belonged to three monophyletic lineages. Species-specific gene duplications, caused mainly by segmental duplication, led to the great expansion of oleosin genes and occurred frequently in eudicots after the monocot–eudicot divergence. Functional divergence analyses indicate that significant amino acid site-specific selective constraints acted on the different clades of oleosins. Adaptive evolution analyses demonstrate that oleosin genes were subject to strong purifying selection after their species-specific duplications and that rapid evolution occurred with a high degree of evolutionary dynamics in the pollen-specific oleosin genes. In conclusion, this study serves as a foundation for genome-wide analyses of the oleosins. These findings provide insight into the function and evolution of this gene family in angiosperms and pave the way for studies in other plants.     

Some physical parameters controlling cell size during the evolution of the procaryons

Possible factors controlling cell size during the evolution of unicellular organisms have been examined. It has been shown that considerations of osmotic and membrane pressure equilibria will predict minimal cell sizes which are in good agreement with those found in present day microorganisms. It has also been shown that the possibility of random proton ‘noise’ would not be a limiting factor for even the smalles organisms or structures. Maximum cell size would be governed by the requirements of diffusion and transport within the cell.     

On the evolution of brain size in relation to migratory behaviour in birds

Migratory birds appear to have relatively smaller brain size compared to sedentary species. It has been hypothesized that initial differences in brain size underlying behavioural flexibility drove the evolution of migratory behaviour; birds with relatively large brains evolved sedentary habits and those with relatively small brains evolved migratory behaviour (migratory precursor hypothesis). Alternative hypotheses suggest that changes in brain size might follow different behavioural strategies and that sedentary species might have evolved larger brains because of differences in selection pressures on brain size in migratory and nonmigratory species. Here we present the first evidence arguing against the migratory precursor hypothesis. We compared relative brain volume of three subspecies of the white-crowned sparrow: sedentary Zonotrichia leucophrys nuttalli and migratory Z. l. gambelii and Z. l. oriantha. Within the five subspecies of the white-crowned sparrow, only Z. l. nuttalli is strictly sedentary. The sedentary behaviour of Z. l. nuttalli is probably a derived trait, because Z. l. nuttalli appears to be the most recent subspecies and because all species ancestral to Zonotrichia as well as all older subspecies of Z. leucophrys are migratory. Compared to migratory Z. l. gambelii and Z. l. oriantha, we found that sedentary Z. l. nuttalli had a significantly larger relative brain volume, suggesting that the larger brain of Z. l. nuttalli evolved after a switch to sedentary behaviour. Thus, in this group, brain size does not appear to be a precursor to the evolution of migratory or sedentary behaviour but rather an evolutionary consequence of a change in migratory strategy.     

A microRNA allele that emerged prior to apple domestication may underlie fruit size evolution

The molecular genetic mechanisms underlying fruit size remain poorly understood in perennial crops, despite size being an important agronomic trait. Here we show that the expression level of a microRNA gene (miRNA172) influences fruit size in apple. A transposon insertional allele of miRNA172 showing reduced expression associates with large fruit in an apple breeding population, whereas over‐expression of miRNA172 in transgenic apple significantly reduces fruit size. The transposon insertional allele was found to be co‐located with a major fruit size quantitative trait locus, fixed in cultivated apples and their wild progenitor species with relatively large fruit. This finding supports the view that the selection for large size in apple fruit was initiated prior to apple domestication, likely by large mammals, before being subsequently strengthened by humans, and also helps to explain why signatures of genetic bottlenecks and selective sweeps are normally weaker in perennial crops than in annual crops.     

Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog Xenopus laevis

Background  

Ancient whole genome duplications have been implicated in the vertebrate and teleost radiations, and in the emergence of diverse angiosperm lineages, but the evolutionary response to such a perturbation is still poorly understood. The African clawed frog Xenopus laevis experienced a relatively recent tetraploidization ~40 million years ago. Analysis of the considerable amount of EST sequence available for this species together with the genome sequence of the related diploid Xenopus tropicalis provides a unique opportunity to study the genomic response to whole genome duplication.     

Survival of the fattest: the key to human brain evolution

The circumstances of human brain evolution are of central importance to accounting for human origins, yet are still poorly understood. Human evolution is usually portrayed as having occurred in a hot, dry climate in East Africa where the earliest human ancestors became bipedal and evolved tool-making skills and language while struggling to survive in a wooded or savannah environment. At least three points need to be recognised when constructing concepts of human brain evolution : (1) The human brain cannot develop normally without a reliable supply of several nutrients, notably docosahexaenoic acid, iodine and iron. (2) At term, the human fetus has about 13 % of body weight as fat, a key form of energy insurance supporting brain development that is not found in other primates. (3) The genome of humans and chimpanzees is <1 % different, so if they both evolved in essentially the same habitat, how did the human brain become so much larger, and how was its present-day nutritional vulnerability circumvented during 5-6 million years of hominid evolution ? The abundant presence of fish bones and shellfish remains in many African hominid fossil sites dating to 2 million years ago implies human ancestors commonly inhabited the shores, but this point is usually overlooked in conceptualizing how the human brain evolved. Shellfish, fish and shore-based animals and plants are the richest dietary sources of the key nutrients needed by the brain. Whether on the shores of lakes, marshes, rivers or the sea, the consumption of most shore-based foods requires no specialized skills or tools. The presence of key brain nutrients and a rich energy supply in shore-based foods would have provided the essential metabolic and nutritional support needed to gradually expand the hominid brain. Abundant availability of these foods also provided the time needed to develop and refine proto-human attributes that subsequently formed the basis of language, culture, tool making and hunting. The presence of body fat in human babies appears to be the product of a long period of sedentary, shore-based existence by the line of hominids destined to become humans, and became the unique solution to insuring a back-up fuel supply for the expanding hominid brain. Hence, survival of the fattest (babies) was the key to human brain evolution.     

Effects of brain and facial size on basicranial form in human and primate evolution

Understanding variation in the basicranium is of central importance to paleoanthropology because of its fundamental structural role in skull development and evolution. Among primates, encephalisation is well known to be associated with flexion between midline basicranial elements, although it has been proposed that the size or shape of the face influences basicranial flexion. In particular, brain size and facial size are hypothesized to act as antagonists on basicranial flexion. One important and unresolved problem in hominin skull evolution is that large-brained Neanderthals and some Mid-Pleistocene humans have slightly less flexed basicrania than equally large-brained modern humans. To determine whether or not this is a consequence of differences in facial size, geometric morphometric methods were applied to a large comparative data set of non-human primates, hominin fossils, and humans (N = 142; 29 species). Multiple multivariate regression and thin plate spline analyses suggest that basicranial evolution is highly significantly influenced by both brain size and facial size. Increasing facial size rotates the basicranium away from the face and slightly increases the basicranial angle, whereas increasing brain size reduces the angles between the spheno-occipital clivus and the presphenoid plane, as well as between the latter and the cribriform plate. These interactions can explain why Neanderthals and some Mid-Pleistocene humans have less flexed cranial bases than modern humans, despite their relatively similar brain sizes. We highlight that, in addition to brain size (the prime factor implicated in basicranial evolution in Homo), facial size is an important influence on basicranial morphology and orientation. To better address the multifactorial nature of basicranial flexion, future studies should focus on the underlying factors influencing facial size evolution in hominins.     

Brain size at birth throughout human evolution: a new method for estimating neonatal brain size in hominins

An increase in brain size is a hallmark of human evolution. Questions regarding the evolution of brain development and obstetric constraints in the human lineage can be addressed with accurate estimates of the size of the brain at birth in hominins. Previous estimates of brain size at birth in fossil hominins have been calculated from regressions of neonatal body or brain mass to adult body mass, but this approach is problematic for two reasons: modern humans are outliers for these regressions, and hominin adult body masses are difficult to estimate. To accurately estimate the brain size at birth in extinct human ancestors, an equation is needed for which modern humans fit the anthropoid regression and one in which the hominin variable entered into the regression equation has limited error. Using phylogenetically sensitive statistics, a resampling approach, and brain-mass data from the literature and from National Primate Research Centers on 362 neonates and 2802 adults from eight different anthropoid species, we found that the size of the adult brain can strongly predict the size of the neonatal brain (r² = 0.97). This regression predicts human brain size, indicating that humans have precisely the brain size expected as an adult given the size of the brain at birth. We estimated the size of the neonatal brain in fossil hominins from a reduced major axis regression equation using published cranial capacities of 89 adult fossil crania. We suggest that australopiths gave birth to infants with cranial capacities that were on average 180 cc (95% CI: 158–205 cc), slightly larger than the average neonatal brain size of chimpanzees. Neonatal brain size increased in early Homo to 225 cc (95% CI: 198–257 cc) and in Homo erectus to approximately 270 cc (95% CI: 237–310 cc). These results have implications for interpreting the evolution of the birth process and brain development in all hominins from the australopiths and early Homo, through H. erectus, to Homo sapiens.