In the Light of Evolution Volume VI: Brain and Behavior (2013) / Chapter Skim
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14 Human Brain Evolution: From Gene Discovery to Phenotype Discovery--Todd M. Preuss
14 Human Brain Evolution: From Gene Discovery to Phenotype Discovery--Todd M. Preuss
Pages 253-272
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From page 253... ...
In part, the difficulty of connecting genes to phenotypes reflects our generally poor knowledge of human phenotypic specializations, as well as the difficulty of interpreting the consequences of genetic changes in species that are not amenable to invasive research. On the positive side, investigations of FOXP2, along with genomewide surveys of gene expression changes and selection-driven sequence changes, offer the opportunity for "phenotype discovery," providing clues to human phe notypic specializations that were previously unsuspected.
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From page 254... ...
A claim about human specializations requires comparing the human species to its sister taxa (chimpanzee and bonobos) , to demonstrate that there are differences between these species, and then comparing the human–chimpanzee–bonobo group vs.
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From page 255... ...
The latter judgement requires evidence about the character states of outgroup taxa, such as other apes and monkeys. For practical reasons, evaluations of human specializations often use a minimal set of comparisons, involving humans, chimpanzees, and macaque monkeys (Inset)
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From page 256... ...
These writings established the expectation that we should be able to discover a few key genetic changes that account for many, if not most, of the phenotypic differences between humans and chimpanzees. NEUROBIOLOGICAL AND BEHAVIORAL BACKGROUND In the classical process of "gene discovery," geneticists start with a conspicuous phenotypic variant of a species, and then carry out mapping studies to identify the genetic locus that harbors the mutant allele.
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From page 257... ...
. Studies of brain tissue acquired postmortem are also revealing human specializations of the cellular and histological organization of the cortex (Sherwood et al., 2008; Preuss, 2010)
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From page 258... ...
The resulting studies have compared humans with chimpanzees and other primates on nearly every imaginable dimension of genetics and molecular biology. These include studies that used high-throughput techniques to identify human specializations of gene expression, primarily in the brain, including whole-genome screens to identify genes that underwent humanspecific sequence changes as a result of selection; studies of chromosome segment duplications; identification of differences in alternative splicing between humans and chimps; and more [reviewed in Preuss et al.
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From page 259... ...
There is at least one example, however, of a gene that underwent selection-driven sequence change in human evolution and is related to a human-specific cognitive and behavioral phenotype: FOXP2. The history of the discovery of this gene, its connection to speech and language, and the research inspired by the discovery, illustrate the range of approaches now available to scientists pursuing the genetic underpinnings of human nature, as well as the elusive character of the relationship between single genes and complex phenotypes.
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From page 260... ...
. Other motor-related structures also show reduced gray matter bilaterally, including the cerebellum and the cortex of the precentral gyrus, as does the inferior frontal gyrus (Broca's area)
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From page 261... ...
likely to be related to orofacial movements. Notably, however, in the structural and functional imaging studies, the differences between affected KE family members and unaffected members were not limited to those structures, but involved additional and extensive regions of cortex not usually associated with motor (or language)
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From page 262... ...
[Interestingly, at approximately the same time, two other groups independently reported that FOXP2 is among the genes likely to have undergone positive selection in human evolution, based on the ratio of nonsynonymous to synonymous nucleotide changes (Ka/Ks) in genes for which sequence information was available for humans, chimpanzees, and other species (Clark et al., 2003; Zhang et al., 2002a)
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From page 263... ...
. Particular attention has been paid to zebra finches, a favorite species for students of bird song because the male develops its song at sexual maturity, the animal gradually shaping its song to match the memory of a tutor's song (usually that of its father)
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From page 264... ...
Comparative studies of FOXP2, therefore, draw no clear connection between specific sequence changes and vocal learning capacities, although the increased levels of FOXP2 expression reported in birds during periods of song acquisition suggests that this transcription factor is involved in learning-related neural changes. FOXP2: Mouse Model of R552H Substitution One approach that has been adopted to understand the function of FOXP2 in humans is to make mouse models that express the mutant form of FOXP2 present in affected members of the KE family (R552H)
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From page 265... ...
(2007) identified 285 gene targets in fetal human tissue from the inferior frontal gyrus and basal ganglia, and determined their representation in gene ontology (GO)
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From page 266... ...
also showed evidence of positive selection in human evolution. A comparison of published datasets identified 47 gene targets of FOXP2 that were differentially expressed in the cortex of humans and chimpanzees, including a number of genes involved in neural development, central nervous system patterning, and neural transmission.
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From page 267... ...
It could also be the case that FOXP2 has a speech- or language-specific function in the human brain, by virtue of the action of other transcription factors that bind to the same promoters in brain cells targeted by human FOXP2. However, then we would be talking about the interactions of genes involved in building a human organism, rather than a single gene, and it still would not be clear, without additional evidence, that the amino acid substitutions in FOXP2 were selected for their effects on developmental pathways specific to language.
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From page 268... ...
This raises a matter of serious concern: our lack of direct information about the human organism. I have noted the lack of detailed accounts of the human neurobiological and psychological phenotypes, and I think it would be fair to say we are quite ignorant about many other human- specific features of human biology, including human-specific modifications of the developmental programs that generate human-specific phenotypes.
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From page 269... ...
Phenotype discovery starts with species differences in genes or gene expression, identified through gene discovery, comparative genomics, or other comparative molecular methods, and proceeds to identify the biochemical, cell-biological, and other phenotypic consequences of the genetic differences.
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From page 270... ...
. That does not mean we should abandon phenotype-driven gene discovery studies, but gene-driven phenotype discovery may represent an approach with a greater payoff, at least in the short term, and has the additional advantage of being able to reveal previously unsuspected aspects of human nature.
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From page 271... ...
Human Brain Evolution: From Gene Discovery to Phenotype Discovery / 271 ACKNOWLEDGMENTS This work was supported by James S McDonnell Foundation Grant 21002093 and a Yerkes Base Grant from the National Institutes of Health (formerly Grant P51RR000165-51, currently Office of Research Infrastructure Programs/OD Grant P51OD11132)
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