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Reposted by Simon Fisher

Simon Fisher @profsimonfisher.bsky.social · 4d

Twenty-four years ago today, our paper “A forkhead-domain gene is mutated in a severe speech and language disorder” was published: www.nature.com/articles/350....
A personal thread about the ups & downs of the journey we took to get to that point....1/n
🗣️🧬🧪

Image shows the first two printed pages of the paper “A forkhead-domain gene is mutated in a severe speech and language disorder” by Cecilia Lai and colleagues, published in Nature in 2001 (volume 413, pages 519-523). The abstract reads as follows:
Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7. We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.

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Simon Fisher @profsimonfisher.bsky.social · 3d

FOXP2 became a jumping-off point for fascinating research in a range of fields: neuroscience, developmental biology, animal behaviour, evolutionary anthropology & beyond. It has also taught me lots about the challenges of communicating across disciplines. But that’s a story for another thread.
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Human Genetics: The Evolving Story of FOXP2

FOXP2 mutations cause a speech and language disorder, raising interest in potential roles of this gene in human evolution. A new study re-evaluates genomic variation at the human FOXP2 locus but finds...

www.cell.com

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Simon Fisher @profsimonfisher.bsky.social · 3d

In the years that followed, rare FOXP2 disruptions have been found in multiple other families with problems in speech, language & behaviour, refining understanding of the associated disorder, while the impacts of its dysfunction have been studied in detail in animal models & cellular systems. 17/n

Schematic image showing diverse approaches that have been used for studying the roles of the FOXP2 gene in the brain over past couple of decades. The lefthand panel shows a pedigree diagram of the three-generation KE family, investigations of whom led to discovery of the first FOXP2 mutation. The middle panel shows molecular functions of FOXP2, how it interacts with multiple other proteins and regulates chromatin condensation and aspects of neuronal maturation. The righthand panel shows its effects on neurobiological pathways and behaviour as identified in animal models such as mice and songbirds, with a focus on the cortex, striatum and cerebellum of the brain. Figure 1 from the paper “Genetic pathways involved in human speech disorders” by Joery den Hoed and Simon Fisher, published in Current Opinion in Genetics and Development in 2020 (volume 65, pages 103 to 111).

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Simon Fisher @profsimonfisher.bsky.social · 4d

Based on its DNA-binding motif, this was a novel FOX transcription factor, & it was given the official name FOXP2. Prior literature had linked pathogenic variants in other FOX genes to a range of diseases. Our work suggested FOXP2 dysfunction as one potential cause of speech/language disorder. 16/n

Amino-acid sequences of the forkhead domains of three FOXPs, aligned with representative proteins from several branches of FOX transcription factor proteins. All sequences are from Homo sapiens. Residues that are invariant in this selection of forkhead proteins are given beneath the alignment. Asterisks show sites of the substitution mutations in FOXC1, FOXE1 and FOXP3 that had been previously implicated in human disease states. The upwards arrow indicates the site of the R553H substitution identified in FOXP2 in affected members of the KE pedigree. The proposed structure of the forkhead domain as established by X-ray crystallography is shown, containing three α-helices, three β-strands, and two ‘wings’. Figure 4 from the paper “A forkhead-domain gene is mutated in a severe speech and language disorder” by Cecilia Lai and colleagues, published in Nature in 2001 (volume 413, pages 519-523).

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Simon Fisher @profsimonfisher.bsky.social · 4d

When we sequenced this newly discovered section of the gene in the KE family, we found a single nucleotide variant (guanine-to-adenine) in all the affected members, yielding an amino-acid change (arginine-to-histidine) at a critical place in the FOX domain, predicted to disrupt its function. 15/n

Image shows example Sanger DNA sequencing traces for one part of FOXP2 in unaffected (top) and affected (bottom) members of the KE family. The sequencing uncovered a guanine-to-adenine (G-to-A) transition that leads to an R553H substitution in the forkhead domain of the encoded protein in the affected individuals. All affected individuals from the KE pedigree are heterozygous for this variant, whereas all unaffected individuals are homozygous for the reference version. Adapted from Figure 3 in the paper “A forkhead-domain gene is mutated in a severe speech and language disorder” by Cecilia Lai and colleagues, published in Nature in 2001 (volume 413, pages 519-523).

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Simon Fisher @profsimonfisher.bsky.social · 4d

Then, another twist! Turned out that CAGH44 was mischaracterized by the team who had originally cloned it. Our data showed that the gene extends much further than they had thought. Reconstructing the entire locus, we found a key part encoding a forkhead box (FOX), a type of DNA-binding domain. 14/n

Representation of the basic human FOXP2 gene structure on chromosome 7. Boxes represent exons, with positions of initiation and termination codons indicated. The scale shown applies only to exons; the entire region depicted spans more than 267 kb of genomic DNA. Exons encoding polyglutamine tracts (PolyQ) and the forkhead domain (FOX) are indicated. The previously known CAGH44 transcript only covered exons 2–7, missing a large part of the gene. Bacterial artificial chromosome genomic sequence entries are aligned beneath the gene structure. Part of Figure 2 in the paper “A forkhead-domain gene is mutated in a severe speech and language disorder” by Cecilia Lai and colleagues, published in Nature in 2001 (volume 413, pages 519-523).

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Simon Fisher @profsimonfisher.bsky.social · 4d

This unrelated child had a translocation involving exchange of material between chromosomes 7 & 5. We mapped the chromosome 7 breakpoint to our region of interest, very close to CAGH44, a brain-expressed polyglutamine-tract gene. But alas we did not find any changes in CAGH44 in the KE family. 13/n

Microscope images showing the chromosomes of a child who carried a genomic rearrangement - a translocation involving chromosomes 7 and 5. The child was unrelated to the KE family but showed a very similar speech and language disorder to them. The locations of the chromosomal breakpoints are visualized here using a special cytogenetics technique known as metaphase fluorescence in-situ hybridization. Part of Figure 4 in the paper “The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder” by Cecilia Lai and colleagues, published in the American Journal of Human Genetics in 2000 (volume 67, pages 357 to 368)

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Simon Fisher @profsimonfisher.bsky.social · 4d

Cecilia Lai, a PhD student in the lab, began screening promising genes for disruptive variants. Then, plot twist! Jane Hurst, lead author of the first KE-family report, phoned me with the news that she had identified an unrelated case with a similar disorder & a rearrangement of chromosome 7.
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Simon Fisher @profsimonfisher.bsky.social · 4d

Our genomic region of interest was big, only partially characterized & likely to include many unknown genes. It was 1998, some years before the Human Genome Project finished a first draft. As sections of sequence became available, I used bioinformatic approaches to build maps of the interval. 11/n

Image shows a bioinformatic map aligning contiguous sections of sequence data corresponding to one part of chromosome 7, with respect to a set of known genetic markers. One of the bottom rows shows individual protein-coding genes that were predicted by analysing the DNA sequence information. Taken from Figure 2 of the paper “The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder” by Cecilia Lai and colleagues, published in the American Journal of Human Genetics in 2000 (volume 67, pages 357 to 368)

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Simon Fisher @profsimonfisher.bsky.social · 4d

But even as debates ensued on the nature of the disorder, DNA-based methods hadn’t yet been used to test if its inheritance was truly monogenic. By tracing transmission of genetic markers in the family, we confirmed involvement of a single locus, & localized it to one part of chromosome 7.
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Image shows first two printed pages of “Localisation of a gene implicated in a severe speech and language disorder” by Simon Fisher and colleagues, published in Nature Genetics in 1998 (volume 18, pages 168 to 170). The abstract reads:
Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.

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Simon Fisher @profsimonfisher.bsky.social · 4d

The London team countered the claim; in-depth work by neuroscientists Faraneh Vargha-Khadem & @kateewatkins.bsky.social showed the most profound feature of the KE family disorder is impaired sequencing of mouth/face movements underlying speech, with multiple aspects of language also affected. 9/n

The image shows Table 1 from a paper by Faraneh Vargha-Khadem and colleagues, published in the Proceedings of the National Academy of Sciences in 1995 (volume 92, pages 930 to 933). The Table displays comparisons of performance of affected and unaffected members of the KE family on a wide array of different tests of language skills, finding significant differences for almost every aspect tested.

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Simon Fisher @profsimonfisher.bsky.social · 4d

Long before anyone started studying the DNA, reports of the family fueled controversy over existence of a dubious “grammar gene”. Extensive coverage had been given to linguist Myrna Gopnik’s claim of a selective deficit in grammar skills e.g. that KEs “lack a general rule for producing plurals”. 8/n

The left-hand side of the image shows the one-page correspondence that the Canadian linguist Myrna Gopnik wrote to Nature in 1990 (volume 344, page 715) arguing that members of the KE family have a selective deficit in “the accurate usage of syntactical-semantic features of language, such as the significance of number, gender, animacy, proper names, tense and aspect” and that they “lack a general rule for producing plurals”.
The right-hand side of the image shows the “wug” test, one of the tests that Gopnik refers to in her correspondence, highlighted as something that affected KE family members fail on. The top part shows a single simply-drawn imaginary animal, with the text “This is a wug” underneath. The bottom part shows two of these imaginary animals side by side, accompanied by the text “Now there is another one. There are two of them. There are two ......”. The person being tested has to respond by completing correctly the end of this statement (i.e. producing the plural “wugs”).

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Simon Fisher @profsimonfisher.bsky.social · 4d

Unusually, the disorder seemed to be inherited in a classic monogenic dominant pattern, meaning it might be due to disruption of just one genetic locus. I’d read about this very family in a popular science book (Pinker’s “The Language Instinct”) & jumped at the chance to analyse their DNA. 7/n

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Simon Fisher @profsimonfisher.bsky.social · 4d

Soon after we had begun building up cohorts for the project, Tony was contacted by Marcus Pembrey, a leading geneticist at London’s Institute of Child Health. His team had identified a 3-generation British family (codename KE) in which 15 relatives had problems with speech/language development. 6/n

Image shows a pedigree diagram (i.e. family tree) for the KE family, across three successive generations. As is standard for these types of diagrams, it uses squares to indicate males and circles to indicate females, with generations arranged from top to bottom. 15 of the family members are shaded in black, which is used to show that they are affected with a developmental speech & language disorder, while the remaining relatives are unaffected. The pattern of inheritance (about half members of each generation affected, males and females in similar number) appears consistent with a classic monogenic (single-gene) dominant mode of transmission, of the kind you might see in a human genetics textbook.

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Simon Fisher @profsimonfisher.bsky.social · 4d

Twin studies had made clear that inherited factors contribute to childhood speech, language, & reading problems. But we expected a complex genetic architecture, involving effects of multiple different genes. To detect such effects reliably, we would need to analyse data from lots of families. 5/n

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Simon Fisher @profsimonfisher.bsky.social · 4d

In his lab at the Wellcome Trust Centre for Human Genetics, Tony was taking gene-mapping methods that had successfully resolved inherited medical conditions & applying them to human behavioural/cognitive traits. My assigned mission concerned developmental disorders of spoken & written language. 4/n

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Simon Fisher @profsimonfisher.bsky.social · 4d

Pursuing a PhD in this area, I had opportunities to apply the strategy myself & identified a gene mutated in a rare kidney-stone disease. Then in 1996 I was lucky enough to be recruited as postdoc by Anthony Monaco, a much-admired pioneer of human gene discovery, to join a new research program. 3/n

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Simon Fisher @profsimonfisher.bsky.social · 4d

Learning about human genetics as an undergraduate student, I found one emerging area of the field especially enticing. Scientists were discovering the causes of major inherited disorders purely by analysing DNA from affected families, without needing prior knowledge of the biological pathways. 2/n

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Simon Fisher @profsimonfisher.bsky.social · 4d

Twenty-four years ago today, our paper “A forkhead-domain gene is mutated in a severe speech and language disorder” was published: www.nature.com/articles/350....
A personal thread about the ups & downs of the journey we took to get to that point....1/n
🗣️🧬🧪

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Simon Fisher @profsimonfisher.bsky.social · 4d

Not gonna lie, just tried swiping to scroll to next page of a thesis that I'm reading, was surprised by lack of response, & only then did brain kick in to remind me it's a printed copy, & that's not how books work. Time for a break perhaps. 😬

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Reposted by Simon Fisher

Simon Fisher @profsimonfisher.bsky.social · 11d

New analysis of a 1-million yr old fossil skull captured worldwide media attention this week, with many headlines saying it requires a complete rewrite/rethink of human evolution. This is an intriguing study & it's brilliant to see so much public enthusiasm for deciphering our origins, but....1/n 🧪

Image shows just two example headlines from prominent media outlets earlier this week, heralding a newly published discovery that supposedly "rewrites human evolution". Left side, from the BBC: "Million-year-old skull rewrites human evolution, scientists claim"; right side, from the New York Post: "1M-year-old skull discovery could change everything we know about human evolution".

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Simon Fisher @profsimonfisher.bsky.social · 5d

Unique opportunity to direct your own innovative long-term research programme on the psychology of language at @mpi-nl.bsky.social, a leading interdisciplinary Max Planck Institute in Nijmegen, the Netherlands. Nominate yourself or a colleague by 19 December 2025. Please help us spread the word. 👇🧪

Max Planck Institute for Psycholinguistics @mpi-nl.bsky.social · 5d

We're seeking the next Director of the Max Planck Institute for Psycholinguistics! Lead cutting-edge research in language & cognition. Nominations (incl. self) due 19 Dec 2025.
mpi.nl/career-education/vacancies/vacancy/nominations-and-self-nominations-sought-position-director-max

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Simon Fisher @profsimonfisher.bsky.social · 7d

Here's a nice clear explainer of the main findings from the new autism study, by @hannahdevlin.bsky.social, including comments from @utafrith.bsky.social.

Autism should not be seen as single condition with one cause, say scientists

Those diagnosed as small children typically have distinct genetic profile from those diagnosed later, study finds

www.theguardian.com

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Simon Fisher @profsimonfisher.bsky.social · 7d

"Earlier- & later-diagnosed autism have different developmental trajectories & genetic profiles. The findings have important implications for how we conceptualize autism & provide a model to explain some of its diversity." @vw1234.bsky.social & an international team report today in @nature.com: 👇🧪

Polygenic and developmental profiles of autism differ by age at diagnosis - Nature

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

www.nature.com

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Simon Fisher @profsimonfisher.bsky.social · 10d

Note also that in his Congress address about rewriting evolution, Pence treated the famous “March of Progress” image as a direct depiction of Darwinian theory (hence his incorrect claim that we're taught evolution must be linear). I've posted before👇 on this fallacy & how it leads people astray. 5/5

Simon Fisher @profsimonfisher.bsky.social · Jan 3

First, an instantly recognizable image that, in our collective consciousness, has become inextricably tied to the very concept of evolution itself. Tragically for one of the most famous scientific illustrations ever, the image is fundamentally flawed, & a potent driver of fallacy. 2/9

Two pages from the multipage foldout entitled “The Road to Homo Sapiens” created by Rudolph Zallinger in 1965, depicting a sequence of figures of primates from the fossil record, lined up as though they are marching in a parade from left to right, with the pose shifting from walking on all fours towards a more upright stance. The left-hand page shows three ape ancestors from 15–8 million years ago: Dryopithecus, Oreopithecus, and Ramapithecus. The right-hand page shows three recent hominin figures labeled as Neanderthal, Cro-Magnon, and Modern Man.

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