Transcript FOXP2: the language gene

FOXP2: the language gene
Talk of genetics and vice versa
• Steven Pinker
• Commentary on Lai et al.
• The possibility that human language ability has
genetic roots was raised about 40 years ago by
the linguist Noam Chomsky and the neurologist
Eric Lindberg.
• Chomsky noted that language is universal,
complex, and rapidly acquired by children
without explicit instruction.
• Lindberg noted that a small number of children
fail to display this ability, and that sometimes
such deficits run in families.
• Deficits of this kind are now called ‘specific
language impairment’, an umbrella term for
language disorders that cannot be attributed to
retardation, autism, deafness, or other general
causes.
• Specific language impairment is more
concordant in identical twins than in fraternal
twins, indicating a heritable component.
• The inheritance pattern is usually complex, and
until recently poorly understood.
• In 1990, researchers described the 3-generation
KE family, half of whom have a speech and
language disorder.
• The disorder is distributed in the family in a way
that suggests it is caused by a dominant gene
on an autosomal (non-sex) chromosome.
• Skeptics suggested that the gene merely lowers
intelligence or makes speech unintelligible, or
that the disorder is nothing more than an artifact
of a working-class dialect.
• Testing suggested that the disorder is more
complex.
• Affected family members do tend to score lower
on average in IQ tests.
• But the language impairment cannot be a simple
consequence of low intelligence, because some
of the affected members score in the normal
range, and some score higher than their
unaffected relatives.
• Although the affected members have problems
in articulating speech sounds and in controlled
movements of the mouth and tongue, their
language disorder cannot be reduced to a
problem with motor control.
• They also have trouble identifying basic speech
sounds, understanding sentences, judging
grammaticality, and other language skills.
• For example, as adults they have difficulty with a
task involving nonsense words that most 4-yearolds perform easily: completing sequences such
as ‘Every day I plam; yesterday I ____’.
A forkhead-domain gene is
mutated in a severe speech and
language disorder.
• Lai , C. S. L. et al.
• Lai and colleagues studied the KE family in which a
severe speech and language disorder is transmitted as
an autosomal dominant single-gene trait.
• Affected family members have a severe impairment in
the selection and sequencing of fine orofacial
movements, which are necessary for articulation.
• The disorder is also characterized by deficits in several
aspects of language processing, such as the ability to
break up words into their constituent phonemes and
grammatical skills including production and
comprehension of word inflections and syntactical
structure.
• In previous work, they found that the gene
mapped to a region 7q31 on chromosome 7.
• Lai et al. found an individual CS, unrelated to the
KE family, who had a very similar speech
disorder.
• When they examined the 7q31 region of CS,
they found a chromosome translocation that
disrupted a gene that they subsequently named
FOXP2.
• They went back to examine the FOXP2 in
the KE family, they found a single
mutation, a G-to-A SNP in exon 14, that
was present in all affected individuals and
absent in all unaffected individuals.
• Lai et al. found that the mutation was
absent in 364 chromosomes from
unrelated Caucasian controls.
• The FOXP2 gene is a member of the FOX
family of transcription factors (genes that
regulate the transcription of other genes).
• The G-to-A SNP in exon 14 of FOXP2 is in
a region that controls binding of FOXP2 to
the DNA. It is invariant in all the currently
known member of the FOX family, in
species ranging from yeast to human.
• Lai et al. suggest that the mutation
observed in KE family members affects
the DNA-binding or transcription properties
of FOXP2.
• FOXP2 is the first gene to have been
implicated in the development of neural
structures that are important for speech
and language.
FOXP2 expression during brain
development coincides with adult
sites of pathology in a severe
speech and language disorder.
Lai , C. S. L. et al.
• In vivo imaging technologies have developed
that allow structural and functional
neuroimaging.
• MRI and PET revealed several abnormal brain
structures in affected KE family members,
compared with unaffected controls.
• Lai et al decided to examine the expression of
FOXP2 during brain development in mice and
humans, and to compare it to abnormalities
identified by imaging or suggested by regions
known to be involved in language and motor
control.
• FOXP2 expression in the developing brain
was not uniform or diffuse, but neither is it
limited to any one brain area.
• Instead, it shows restricted expression in a
number of brain areas.
• Many brain areas, such as the
hippocampus, do not have detectable
FOXP2.
• FOXP2 is expressed in motor-related circuits
during brain development.
• In addition to expression in the developing
cortical plate, FOXP2 expression during CNS
development is found predominantly in a series
of neural circuits that have been implicated in
motor control, including the basal ganglia,
thalamus, inferior olives, and the cerebellum.
• These structures are intricately interconnected to
subserve motor-related functions.
• The basal ganglia modulate activity of premotor
and prefrontal cortical areas via complex
projections through the globus pallidus,
substantia nigra, and the thalamus
• The cerebellum plays an important role in
regulating motor coordination, receiving input
from the inferior olives.
• Lai’s expression data implicating FOXP2 in the
development of corticostriatal and
olivocerebellar motor-related circuits during
embryogenesis may account for the oromotor
problems of humans with FOXP2 mutations.
• It is possible that the accompanying linguistic
and grammatical impairments in the KE family
are secondary consequences of basic deficits in
motor planning and sequencing.
• However, it is equally plausible that the motor
and cognitive problems arise simultaneously.
• There is growing appreciation that area
traditionally considered to be purely motor also
contribute to cognitive and complex behavior.
• The exclusively motoric nature of the caudate
nucleus is challenged by data supporting roles in
procedural learning and memory.
• Similarly, it is now recognized that the
cerebellum and prefrontal cortex form neural
circuits with both motor and cognitive
capabilities.
• Thus, Lai’s data are consistent with the
emerging view that subcortical structures play a
significant role in linguistic functioning.
• FOXP2 expression in sites of pathology
identified by brain imaging
• Lai’s observation of FOXP2 expression in the
developing caudate nucleus of the embryo is
paralleled by neuroimaging studies in the KE
family.
• A bilateral reduction of grey matter density in the
caudate nucleus has been found in affected
individuals. A PET study showed over-activation
of the caudate nucleus in two affected
individuals when performing a word repetition
task.
• FOXP2 mutation is also associated with
significant structural abnormalities in the
cerebellum, where Lai et al. found strong
expression during embryonic development.
• Studies of unrelated patients with acquired
lesions highlight a cerebellar rle in procedural
learning, particularly in detection and generation
of event sequences and in linguistic functions.
• FOXP2 expression patterns are highly
concordant in mouse and human brain
development
• Lai et al. found a high degree of similarity
between mouse and human FOXP2 expression
patterns in the developing CNS.
• They did not find any evidence for regions of
FOXP2 expression that are only observed in
humans in early brain development.
• These data suggest that FOXP2 may be
generally implicated in aspects of motor control
in mammalian species, and was already playing
a role in the development of motor-related brain
regions in the human-mouse common ancestor.
• Thus, positive selection of FOXP2 mutations in
recent human history probably involved
modifications to pre-existing brain systems,
rather than acquisition of novel ones.
Molecular evolution of FOXP2, a
gene involved in speech and
language.
• Enard W, Przeworski M, Fisher SE, Lai
CS, Wiebe V, Kitano T, Monaco AP,
Paabo S
• The ability to develop articulate speech relies on
capabilities, such as fine control of the larynx
and mouth1, that are absent in chimpanzees
and other great apes.
• Enard et al. sequenced the complementary
DNAs that encode the FOXP2 protein in the
chimpanzee, gorilla, orang-utan, rhesus
macaque and mouse, and compared them with
the human cDNA.
• They also investigated intraspecific variation of
the human FOXP2 gene.
• Enard et al. show that human FOXP2 contains changes
in amino acid coding and a pattern of nucleotide
polymorphism that strongly suggest that this gene has
been the target of selection during recent human
evolution.
• FOXP2 (forkhead box P2) is located on human
chromosome 7q31, and its major splice form encodes a
protein of 715 amino acids belonging to the forkhead
class of transcription factors2.
• It contains a glutamine-rich region consisting of two
adjacent polyglutamine tracts, encoded by mixtures of
CAG and CAA repeats.
• Such repeats are known to have elevated mutation
rates.
• In the case of FOXP2, the lengths of the polyglutamine
stretches differed for all taxa studied.
• Variation in the second polyglutamine tract has been
observed in a small family affected with speech and
language impairment, but this did not co-segregate with
disorder, suggesting that minor changes in length may
not significantly alter the function of the protein4.
• If the polyglutamine stretches are disregarded, the
human FOXP2 protein differs at only three amino-acid
positions from its orthologue in the mouse.
• When compared with a collection of 1,880 human–
rodent gene pairs5, FOXP2 is among the 5% mostconserved proteins.
• The chimpanzee, gorilla and rhesus macaque FOXP2
proteins are all identical to each other and carry only one
difference from the mouse and two differences from the
human protein, whereas the orangutan carries two
differences from the mouse and three from humans.
• Thus, although the FOXP2 protein is highly conserved,
two of the three amino-acid differences between humans
and mice occurred on the human lineage after the
separation from the common ancestor with the
chimpanzee.
• These two amino-acid differences are both
found in exon 7 of the FOXP2 gene and
are a threonine-to-asparagine and an
asparagine-to-serine change at positions
303 and 325, respectively.
• Enard et al. compared the FOXP2 protein
structures predicted by a variety of
methods for humans, chimpanzees,
orangutans and mice.
• The chimpanzee and mouse structures
were essentially identical and the
orangutan showed only a minor change in
secondary structure
• The human-specific change at position
325 creates a potential target site for
phosphorylation by protein kinase C
together with a minor change in predicted
secondary structure.
• Several studies have shown that
phosphorylation of forkhead transcription
factors can be an important mechanism
mediating transcriptional regulation.
• Thus, although the FOXP2 protein is
extremely conserved among mammals, it
acquired two amino-acid changes on the
human lineage, at least one of which may
have functional consequences.
• To investigate whether the amino acids
encoded in exon 7 are polymorphic in
humans, Enard et al. sequenced this exon
from 44 human chromosomes originating
from all major continents.
• In no case was any amino-acid
polymorphism found.
• They analyzed the complete coding region of
FOXP2 in 91 unrelated individuals of mainly
European descent found no amino-acid
replacements except for one case of an insertion
of two glutamine codons in the second
polyglutamine stretch4.
• Because the two amino-acid variants specific to
humans occur in 226 human chromosomes, this
suggests that they are fixed among humans.
• The evolutionary lineages leading to
humans and mice diverged about 70
million years (Myr) ago.
• Thus, during the roughly 130 Myr of
evolution that separate the common
ancestor of humans and chimpanzees
from the mouse, a single amino-acid
change occurred in the FOXP2 protein.
• By contrast, since the human and
chimpanzee lineages diverged about 4.6–
6.2 Myr ago11, two fixed amino-acid
changes occurred on the human lineage
whereas none occurred on the
chimpanzee and the other primate
lineages, except for one change on the
orang-utan lineage.
• Enard et al. speculate that some human-specific
feature of FOXP2, perhaps one or both of the
amino-acid substitutions in exon 7, affect a
person’s ability to control orofacial movements
and thus to develop proficient spoken language.
• If this speculation is true, then the time when
such a FOXP2 variant became fixed in the
human population may be pertinent with regard
to the evolution of human language.
• Under a model of a randomly mating population
of constant size, the most likely date since the
fixation of the beneficial allele is 0, with
approximate 95% confidence intervals of 0 and
120,000 years.
• Inclusion of population growth may push this
time estimate back by at most the time since the
onset of human population growth, some
10,000–100,000 years ago.
• The method suggests that the fixation
occurred during the last 200,000 years of
human history, that is, concomitant with or
subsequent to the emergence of
anatomically modern humans.
• This is compatible with a model in which
the expansion of modern humans was
driven by the appearance of a moreproficient spoken language.