Kimberly L Cooper1. 1. Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093-0377, USA.
Abstract
The variety of limb skeletal proportions enables a remarkable diversity of behaviors that include powered flight in bats and flipper-propelled swimming in whales using extremes of a range of homologous limb architectures. Even within human limbs, bone lengths span more than an order of magnitude from the short finger and toe bones to the long arm and leg bones. Yet all of this diversity arises from embryonic skeletal elements that are each a very similar size at formation. In this review article, I survey what is and is not yet known of the development and evolution of skeletal proportion at multiple hierarchical levels of biological organization. These include the cellular parameters of skeletal elongation in the cartilage growth plate, genes associated with differential growth, and putative gene regulatory mechanisms that would allow both covariant and independent evolution of the forelimbs and hindlimbs and of individual limb segments. Although the genetic mechanisms that shape skeletal proportion are still largely unknown, and most of what is known is limited to mammals, it is becoming increasingly apparent that the diversity of bone lengths is an emergent property of a complex system that controls elongation of individual skeletal elements using a genetic toolkit shared by all.
The variety of limb skeletal proportions enables a remarkable diversity of behaviors that include powered flight in bats and flipper-propelled swimming in whales using extremes of a range of homologous limb architectures. Even within human limbs, bone lengths span more than an order of magnitude from the short finger and toe bones to the long arm and leg bones. Yet all of this diversity arises from embryonic skeletal elements that are each a very similar size at formation. In this review article, I survey what is and is not yet known of the development and evolution of skeletal proportion at multiple hierarchical levels of biological organization. These include the cellular parameters of skeletal elongation in the cartilage growth plate, genes associated with differential growth, and putative gene regulatory mechanisms that would allow both covariant and independent evolution of the forelimbs and hindlimbs and of individual limb segments. Although the genetic mechanisms that shape skeletal proportion are still largely unknown, and most of what is known is limited to mammals, it is becoming increasingly apparent that the diversity of bone lengths is an emergent property of a complex system that controls elongation of individual skeletal elements using a genetic toolkit shared by all.
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Dmitry Shungin; Alena Stancáková; Rona J Strawbridge; Yun Ju Sung; Toshiko Tanaka; Alexander Teumer; Stella Trompet; Sander W van der Laan; Jessica van Setten; Jana V Van Vliet-Ostaptchouk; Zhaoming Wang; Loïc Yengo; Weihua Zhang; Uzma Afzal; Johan Arnlöv; Gillian M Arscott; Stefania Bandinelli; Amy Barrett; Claire Bellis; Amanda J Bennett; Christian Berne; Matthias Blüher; Jennifer L Bolton; Yvonne Böttcher; Heather A Boyd; Marcel Bruinenberg; Brendan M Buckley; Steven Buyske; Ida H Caspersen; Peter S Chines; Robert Clarke; Simone Claudi-Boehm; Matthew Cooper; E Warwick Daw; Pim A De Jong; Joris Deelen; Graciela Delgado; Josh C Denny; Rosalie Dhonukshe-Rutten; Maria Dimitriou; Alex S F Doney; Marcus Dörr; Niina Eklund; Elodie Eury; Lasse Folkersen; Melissa E Garcia; Frank Geller; Vilmantas Giedraitis; Alan S Go; Harald Grallert; Tanja B Grammer; Jürgen Gräßler; Henrik Grönberg; Lisette C P G M de Groot; Christopher J Groves; Jeffrey Haessler; Per Hall; Toomas Haller; Goran Hallmans; Anke Hannemann; Catharina A Hartman; Maija Hassinen; Caroline Hayward; Nancy L Heard-Costa; Quinta Helmer; Gibran Hemani; Anjali K Henders; Hans L Hillege; Mark A Hlatky; Wolfgang Hoffmann; Per Hoffmann; Oddgeir Holmen; Jeanine J Houwing-Duistermaat; Thomas Illig; Aaron Isaacs; Alan L James; Janina Jeff; Berit Johansen; Åsa Johansson; Jennifer Jolley; Thorhildur Juliusdottir; Juhani Junttila; Abel N Kho; Leena Kinnunen; Norman Klopp; Thomas Kocher; Wolfgang Kratzer; Peter Lichtner; Lars Lind; Jaana Lindström; Stéphane Lobbens; Mattias Lorentzon; Yingchang Lu; Valeriya Lyssenko; Patrik K E Magnusson; Anubha Mahajan; Marc Maillard; Wendy L McArdle; Colin A McKenzie; Stela McLachlan; Paul J McLaren; Cristina Menni; Sigrun Merger; Lili Milani; Alireza Moayyeri; Keri L Monda; Mario A Morken; Gabriele Müller; Martina Müller-Nurasyid; Arthur W Musk; Narisu Narisu; Matthias Nauck; Ilja M Nolte; Markus M Nöthen; Laticia Oozageer; Stefan Pilz; Nigel W Rayner; Frida Renstrom; Neil R Robertson; Lynda M Rose; Ronan Roussel; Serena Sanna; Hubert Scharnagl; Salome Scholtens; Fredrick R Schumacher; Heribert Schunkert; Robert A Scott; Joban Sehmi; Thomas Seufferlein; Jianxin Shi; Karri Silventoinen; Johannes H Smit; Albert Vernon Smith; Joanna Smolonska; Alice V Stanton; Kathleen Stirrups; David J Stott; Heather M Stringham; Johan Sundström; Morris A Swertz; Ann-Christine Syvänen; Bamidele O Tayo; Gudmar Thorleifsson; Jonathan P Tyrer; Suzanne van Dijk; Natasja M van Schoor; Nathalie van der Velde; Diana van Heemst; Floor V A van Oort; Sita H Vermeulen; Niek Verweij; Judith M Vonk; Lindsay L Waite; Melanie Waldenberger; Roman Wennauer; Lynne R Wilkens; Christina Willenborg; Tom Wilsgaard; Mary K Wojczynski; Andrew Wong; Alan F Wright; Qunyuan Zhang; Dominique Arveiler; Stephan J L Bakker; John Beilby; Richard N Bergman; Sven Bergmann; Reiner Biffar; John Blangero; Dorret I Boomsma; Stefan R Bornstein; Pascal Bovet; Paolo Brambilla; Morris J Brown; Harry Campbell; Mark J Caulfield; Aravinda Chakravarti; Rory Collins; Francis S Collins; Dana C Crawford; L Adrienne Cupples; John Danesh; Ulf de Faire; Hester M den Ruijter; Raimund Erbel; Jeanette Erdmann; Johan G Eriksson; Martin Farrall; Ele Ferrannini; Jean Ferrières; Ian Ford; Nita G Forouhi; Terrence Forrester; Ron T Gansevoort; Pablo V Gejman; Christian Gieger; Alain Golay; Omri Gottesman; Vilmundur Gudnason; Ulf Gyllensten; David W Haas; Alistair S Hall; Tamara B Harris; Andrew T Hattersley; Andrew C Heath; Christian Hengstenberg; Andrew A Hicks; Lucia A Hindorff; Aroon D Hingorani; Albert Hofman; G Kees Hovingh; Steve E Humphries; Steven C Hunt; Elina Hypponen; Kevin B Jacobs; Marjo-Riitta Jarvelin; Pekka Jousilahti; Antti M Jula; Jaakko Kaprio; John J P Kastelein; Manfred Kayser; Frank Kee; Sirkka M Keinanen-Kiukaanniemi; Lambertus A Kiemeney; Jaspal S Kooner; Charles Kooperberg; Seppo Koskinen; Peter Kovacs; Aldi T Kraja; Meena Kumari; Johanna Kuusisto; Timo A Lakka; Claudia Langenberg; Loic Le Marchand; Terho Lehtimäki; Sara Lupoli; Pamela A F Madden; Satu Männistö; Paolo Manunta; André Marette; Tara C Matise; Barbara McKnight; Thomas Meitinger; Frans L Moll; Grant W Montgomery; Andrew D Morris; Andrew P Morris; Jeffrey C Murray; Mari Nelis; Claes Ohlsson; Albertine J Oldehinkel; Ken K Ong; Willem H Ouwehand; Gerard Pasterkamp; Annette Peters; Peter P Pramstaller; Jackie F Price; Lu Qi; Olli T Raitakari; Tuomo Rankinen; D C Rao; Treva K Rice; Marylyn Ritchie; Igor Rudan; Veikko Salomaa; Nilesh J Samani; Jouko Saramies; Mark A Sarzynski; Peter E H Schwarz; Sylvain Sebert; Peter Sever; Alan R Shuldiner; Juha Sinisalo; Valgerdur Steinthorsdottir; Ronald P Stolk; Jean-Claude Tardif; Anke Tönjes; Angelo Tremblay; Elena Tremoli; Jarmo Virtamo; Marie-Claude Vohl; Philippe Amouyel; Folkert W Asselbergs; Themistocles L Assimes; Murielle Bochud; Bernhard O Boehm; Eric Boerwinkle; Erwin P Bottinger; Claude Bouchard; Stéphane Cauchi; John C Chambers; Stephen J Chanock; Richard S Cooper; Paul I W de Bakker; George Dedoussis; Luigi Ferrucci; Paul W Franks; Philippe Froguel; Leif C Groop; Christopher A Haiman; Anders Hamsten; M Geoffrey Hayes; Jennie Hui; David J Hunter; Kristian Hveem; J Wouter Jukema; Robert C Kaplan; Mika Kivimaki; Diana Kuh; Markku Laakso; Yongmei Liu; Nicholas G Martin; Winfried März; Mads Melbye; Susanne Moebus; Patricia B Munroe; Inger Njølstad; Ben A Oostra; Colin N A Palmer; Nancy L Pedersen; Markus Perola; Louis Pérusse; Ulrike Peters; Joseph E Powell; Chris Power; Thomas Quertermous; Rainer Rauramaa; Eva Reinmaa; Paul M Ridker; Fernando Rivadeneira; Jerome I Rotter; Timo E Saaristo; Danish Saleheen; David Schlessinger; P Eline Slagboom; Harold Snieder; Tim D Spector; Konstantin Strauch; Michael Stumvoll; Jaakko Tuomilehto; Matti Uusitupa; Pim van der Harst; Henry Völzke; Mark Walker; Nicholas J Wareham; Hugh Watkins; H-Erich Wichmann; James F Wilson; Pieter Zanen; Panos Deloukas; Iris M Heid; Cecilia M Lindgren; Karen L Mohlke; Elizabeth K Speliotes; Unnur Thorsteinsdottir; Inês Barroso; Caroline S Fox; Kari E North; David P Strachan; Jacques S Beckmann; Sonja I Berndt; Michael Boehnke; Ingrid B Borecki; Mark I McCarthy; Andres Metspalu; Kari Stefansson; André G Uitterlinden; Cornelia M van Duijn; Lude Franke; Cristen J Willer; Alkes L Price; Guillaume Lettre; Ruth J F Loos; Michael N Weedon; Erik Ingelsson; Jeffrey R O'Connell; Goncalo R Abecasis; Daniel I Chasman; Michael E Goddard; Peter M Visscher; Joel N Hirschhorn; Timothy M Frayling Journal: Nat Genet Date: 2014-10-05 Impact factor: 38.330
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