Massimo Piattelli-Palmarini University of Arizona Session 5 (and last) (June 16)

1. Netherlands Graduate School of LinguisticsLOT Summer School 2006Issues in the biology and evolution of language Massimo Piattelli-Palmarini University of Arizona Session 5 (and last) (June 16) New perspectives in the biology of language

2. A central consideration • So much has changed in biology • And in linguistic theory • That • I suggest we re-examine the whole issue of the biology of language and of reconstructing language evolution • In search of new “windows of opportunity” New perspectives

3. Foreword: Beyond textbook genetics • Science advances by opening “windows of opportunity” (Nadel & Piattelli-Palmarini 2002) • Mendelian patterns of genetic inheritance that produce neatly identifiable pathological phenotypes have been one such “window” (ever since Archibald E. Garrod’s Inborn Errors of Metabolism - 1908) • Single point mutations in DNA that invariably correspond to identifiable phenotypic variations (phenylketonuria, sickle-cell anemia etc.) • Such cases of high genetic penetrance are the substance of textbook genetics (biochemical pathways, hemoglobin) • But they are not the “typical” or “average” gene • Today, we are in need of other windows • To go beyond this wonderful, but limiting, scheme New perspectives

4. Some paradigmatic historical windows • The motion of celestial bodies • The emission and absorption spectra of gaseous substances • The spontaneous “emanations” of uranium composites • The diffraction of X-rays by organic crystals • The genetics of bacteria and their viruses • Inborn errors of metabolism • The giant squid axon (Hodgkin and Huxley) • The receptive fields of neurons in the primary visual cortex (Hubel and Wiesel) • Grammaticality judgments of native speakers • Mirror neurons New perspectives

5. Another central consideration • Obviously, we want a functional account and an evolutionary reconstruction of mind and language • That is completely “mechanical” • Like the ones, say, for the adaptive immune system, or for the eye • No less “mechanical” than these (all things considered) • But also not more mechanical than these, • Given the known remarkable dynamic subtleties involved. New perspectives

6. The new genetics

7. A brief summary • Master genes (homeoboxes etc.) • The ubiquity of pleiotropic effects (ex. for Otx thecerebral cortex, kidneys, testes, gut lining) • Gene duplication, gene conversion and transposable elements • RNA editing and quality control (chaperonines) • The importance of non-coding sequences • RNA-only genes • Retroposons and SINEs (David Haussler UCSC, conserved from the coelacanth to humans) New perspectives

8. Matthew Ronshaugen, Nadine McGinnis & William McGinnis Nature 2002 “the first experimental evidence that links naturally selected alterations of a specific protein sequence to a major morphological transition in evolution”. High sequence conservation and major phenotypic differences coexist. New perspectives

9. A brief summary - continued • Micro RNAs and Argonaute proteins (ubiquitous gene expression modulators) • The histone code (epigenomics) • DNA methylation • Kissing chromosomes and gene-expression “waves” • Epigenetic mechanisms • Cut and run mRNA (nuclear speckles) • Ancestral DNA caches (revertant variants that have come from one of the great-grandparents, even if the immediate parent did not contain the variant) (Lolle and Pruitt, 2005) • Previously unsuspected degree of individual genetic variation New perspectives

10. Where it all started 1953 New perspectives

11. Classical genetics • DNA sequence-based genetics: the information contained in DNA is all encoded in the sequence • The central dogma of molecular biology: DNA makes RNA makes protein • (Less than 2% of the human genome is made of protein-coding DNA) protein DNA New perspectives

12. A missing dimension: Plasticity fidelity of conversion plasticity of response specificity of information New perspectives

13. The importance of plasticity • differential patterns of gene expression. • Many of these differences arise during development and are subsequently retained through cell division. • Cell fate: a single cell precursor can develop into different cell types. • Cell memory: mother cells can transmit to daughter cells a functional state acquired in response to an endogenous developmental program or exogenous stimuli. • Modifications in cell function induced by the environment. New perspectives

14. New perspectives

15. Main new lessons (so far): • An organism does not inherit a “naked DNA” • But an entire, organized and partially pre-regulated genome (notably including the methylation, acetylation etc. of the histones) • “Through the chromosomes, but outside DNA” • Gene imprinting, norms of response • Most genetic variants have low or moderate penetrance (unlike the textbook cases of inborn errors of metabolism) • The internal (developmental-tissutal) environment and the external environment may produce major differences, some of which are inheritable, and some of which are “non-transitive” • Without any change in DNA sequence. New perspectives

16. Enter Epigenetics • Epigenetics: the study of heritable changes in gene function that occur without a change in the DNA sequence and are therefore potentially reversible. Scientific American, December 2003 New perspectives

17. The case of identical twins DNA sequence: identical multiple sclerosis asthma New perspectives

18. The case of the black mouse DNA sequence: identical The murine agouti gene encodes a signaling molecule that signals follicular melanocytes to switch from producing black eumelanin to yellow phaeomelanin New perspectives

19. Does nutrition matter? Start females on diet (methyl donors and cofactors folic acid, vit B12, anhydrous betaine) offspring rated for coat color mating birth 14 d pregnancy lactation day 21 New perspectives

20. A classic evolutionary puzzle: • a b good • A B even better • But • a B lethal • A b lethal • How do you get to A B ? • Solution: You keep a and b in a DNA “archive” • And then activate A and B only when both are available • Silencing a and b • An evolutionary “capacitor” (S. Lindquist 1998) New perspectives

21. Mutation in the HSP90 genea chaperonine New perspectives

22. Mutation in the HSP90 genea chaperonine, a quality-control gene, a “buffer” gene Hsp90 normally acts to reduce the likelihood that stochastic events will alter the deterministic unfolding of a multitude of developmental programmes. Rutherford, S. L., & Lindquist, S. (1998). Hsp90 as a capacitor for morphological evolution. Nature, 396 (26 November), 336-342. New perspectives

23. Exposes, one generation down the line, pre-existing silent mutations New perspectives

24. Hsp90 N N • Ubiquitous molecular chaperone, i.e. a protein which binds other proteins (“clients”) to help them fold correctly. • Essential to the activation and assembly of a range of client proteins typically involved in signal transduction, cell cycle control and transcriptional regulation. • Works as a molecular “clamp” via transient dimerization of the N-terminal domains. • Recognizes structural features common to unstable proteins and keeps these proteins poised for activation until they are stabilized by modifications associated with signaling. ADP C C ATP N N C C New perspectives

25. Mutation or pharmacological impairment of Drosophila Hsp90 leads to the emergence of phenotypic variation affecting nearly any adult structure. • Multiple, previously silent, genetic determinants produce these variants and become rapidly independent of Hsp90 mutations. • Widespread genetic variation affecting morphogenic pathways exists in nature, but is usually silent. • Hsp90 buffers this variation, allowing it to accumulate under neutral conditions. Nature 1998 capacitor: an electric circuit element used to store charge temporarily New perspectives

26. Evo-Devo role of HSP90 • “Hsp90 stabilizes its ‘client’ proteins in conformations that would otherwise be prone to misfolding and potentiates their capacity to be activated in the proper time and place, by associations with partner proteins, ligand binding, post-translational modifications and correct localization”. • “From the viewpoint of a population geneticist, buffering systems like Hsp90, without regard to any possible adaptive value, would decrease selection on nucleotide substitutions, allowing storage of an expanded spectrum of selectively nearly neutral ones. Under stable environmental conditions, a population arrives at a local fitness optimum in an adaptive landscape.” • “Given that natural selection can only further increase the fitness of a population, it is a perplexing evolutionary question how a population might move to a different local optimum without an intervening period of reduced fitness (adaptive valley)”. New perspectives

27. These authors’ punch line: • “As a by-product of its biochemical function, Hsp90 may allow the neutral accumulation of potentially selectable polymorphisms and synchronize their conversion to a non-neutral state. Certainly, most combinations of polymorphisms will be deleterious, and these may be periodically purged from the population through the environmental coupling of the Hsp90 buffer. However, rare combinations may produce a new, advantageous phenotype, thereby providing a molecular means by which adaptive peak shifts in large populations may occur without passing through an adaptive valley. None of the other mechanisms discussed [genetic drift, compensatory mutations and gene conversion] can be modulated by environmental contingencies”. (Emphasis added) • Christine Queitsch, Todd A. Sangster & Susan Lindquist, Nature (2002) Vol. 417, p. 618 (the effects of HSP90 mutations in Arabidopsis thaliana) New perspectives

28. A crucial lesson: • Mechanism is the name of the game! • Without a mechanism, with descriptions only, you are gasping for scientific air • The case of Waddington’s vein-less flies • The case of Piaget’s lymneas • Not to mention the un-mentionable (Lyssenko and his “vernalization”) • What a “window” typically gives you: Mechanisms! New perspectives

29. New perspectives

30. The histone code active inactive • Histones can be modified by chemical tags attached to their N-terminal tail. • These modifications can then be interpreted by proteins that recognize a particular modification and facilitate the appropriate downstream biological events. New perspectives

31. Epigenetic Mechanisms • The epigenetic status changes in response to developmental and/or environmental cues. • Changes rest mostly on modifications of either the DNA itself (methylation) or of proteins that intimately associate with DNA (histones histone code). methylation acetylation methylation phosphorylation New perspectives

32. Changes in chromatin accessibility dictated bythe histone code govern gene expression enzyme enzyme X silenced active naïve T lymphocytes differentiated T lymphocytes New perspectives

33. Cross-talk between DNA-based andhistone-based epigenetic mechanisms DNA methylationHistone H3-K9 methylation recruitment DNA methylationHistone deacetylation gene silencing New perspectives

34. Frequency of Epigenetic Changes • Epigenetic explanations are quantitatively powerful. • The frequency with which epigenetic modifications arise can reach up to 100% per locus per generation. • By contrast, the rate of DNA sequence mutations is much lower, and varies between 10–5 and 10–9 per locus per generation. • Agiganticdifference in frequency • The impact of epigenetic mechanisms onto phylogenesis and onto a number of common diseases is under intense study New perspectives

35. Evo-devo and the fixation of behaviors • Evolution as the evolution of ontogenies • The 1944-1945 famine in Holland • Early (in ovo) auditory imprinting in birds • Synchrony of egg-hatching and food availability • Childhood maltreatment, monoamine-oxydase A alleles and aggressiveness • 5-HTT serotonine transporter gene (LL, LS and SS variants) childhood experience and depression • maternal-buffering effect in monkeys New perspectives

36. An old consideration • Due to Richard Lewontin: • New behaviors  New environments  New problems to be solved  New selective pressures  new phenotypes • Possibly a genetic fixation of those behaviors • The organism “makes” the environment • Terrence Deacon (1997, 2003) pushes this quite far (E-language, society and the brain co-evolving) New perspectives

37. A general consideration • We have a phenotype P, such that: • Some components are universal in the species • Many, many variants co-exist, a large but finite repertoire • Specific environments canalize the choice of the variant • With binary oppositions • With critical periods (and irreversibility) • No inheritance of the variant • But inheritance of the universal component New perspectives

38. A modern geneticist’s conclusion • P cries out for an epigenetic explanation • And an evolutionary history of fine regulations • WELL • Language is such a P! New perspectives

39. Experience A new look at its nature and role

40. Inter-species conservation and “parameters” • Human Otx genes have been transplanted and expressed in Drosophila (Leuzinger et al., 1998; Nagao et al., 1998) • Conversely, murine Otx genes have been replaced with Drosophila genes, fully rescuing corticogenesis impairment and epilepsy. (Acampora et al. 1998) • These genes are by no means an exception. New perspectives

41. Hox genes tell cells where they are along A-P axis wildtype Antennapedia mutant “homeotic” mutations affect segment identity New perspectives

42. Induction of ectopic eyes by targeted expression of fly eyeless or its mouse homolog Pax-6. Halder et al (1995) Science 276:1788 New perspectives

43. eyeless: master gene controlling eye development • ectopic expression of eyeless in: wing leg antenna PAX6and EYhave very similar structures New perspectives

44. Main lessons • Remarkable, surprising, stunning, (quote,unquote from these papers by geneticists)…. degree of genetic conservation • But also a stunning degree of individual genetic variation • 150 polymorphisms per gene in humans is an average (including the non-coding regions) (1 out of every 100 bases) • Phylogenetic shadowing (SNPs) is redrawing the phylogenetic maps New perspectives

45. 282 The search for “mental retardation” genes” OMiM = Online Mendelian Inheritance in Man (database) 37 245 211 17 17 New perspectives Inlow & Restifo, Genetics, 2004

46. Molecular Functions of Human MR Genes New perspectives Inlow & Restifo, Genetics, 2004

47. How many genes does it take to build a thinking brain? • geneticist’s approach: How many genes can mutate to phenotype that disrupts cognition? eg, mental retardation Hundreds! maybe ~1,000 What biological functions do those genes have at molecular, cellular, tissue levels? • Premise: many genes required to build the brain also required for its adult function • Almost any! How conserved are the genetic programs across species? Remarkably well conserved! (Slide by Prof. Linda Restifo, Division of Neurobiology University of Arizona) New perspectives

48. Parametric variation • A murine PAX-6 gene induces a vertebrate (globular) eye in a vertebrate • But a composite eye (with hundreds of ommatides, a rigorously fixed number) in the fruitfly, • And vice-versa • The “parametric” character of epigenetics • The huge role of “locality” New perspectives

49. Parameters in language

50. The “logical” problem of language acquisition • Suppose the child hears one new sentence type every second • How long would it take (as an average) to her to learn the local grammar correctly? • Robert C. Berwick (of MIT) has made that calculation for a grammar with 100 rules to be “guessed” in a continuum • 150 centuries! 15,000 years! • This is Berwick’s paradox. • So, something totally different must be going on • Parameter fixation as virtually conceptually necessary New perspectives