Sunday, June 20, 2010

Genetic Litany

Chromosome 7q36, engrailed homeobox 2(EN2), the 16p11.2 region, 15q11.2, 15q13.3, 16p13.11; four regions located on 18q (MBD1, TCF4, NETO1, FBXO15); the PON1 gene; MECP2, TM4SF2, TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1; encoding methyl CpG-binding protein 2; the SHANK2 synaptic scaffolding gene; the 5-HT(2A) receptor gene; neurexin-1 (NRXN1), chromosome 17p13.3, the two genes TUSC5 and YWHAE.

Cell adhesion molecule 1 (CADM1); RELN and GRIK2; MKL2 and SND1; chromosome Xp22.11-p21.2 that encompasses the IL1RAPL1 gene; the GABA receptor gamma 3 (GABRG3); neuroligin (NLGN4X); the FMR1 gene; region 10p14-p15, 7p22.1, the Q6NUR6 gene, JMJD2C gene at 9p24.1, 1p21.1, 6p21.3 and 8q21.13; Mecp2-null microglia; R1117X and R536W; SHANK3 mutations, GABA(A) receptor subunits, ASMT, MTNR1A, MTNR1B; RORA and BCL-2 proteins; DOCK4 microdeletion on 7q31.1, 2q14.3 microdeletion disrupting CNTNAP5; chromosome 2q24.2-->q24.3, telencephalic GABAergic neurons, position 614 of diaphanous homolog 3 (DIAPH3), 22q13.3.

Chromosome 2q37, 4q35.1-35.2, 8p23.2; chromosome 8p and 4q, P-glycoprotein gene (MDR1/ABCB1); glutamate transporter gene SLC1A1, IL1RAPL1 gene mutations, neuroligin mutants; SCAMP5, CLIC4 and PPCDC; fatty acid-binding protein (FABP7), 5-HT transporter gene (HTT, SERT, SLC6A4); proteins neurexin1 and PSD95; Cav3.2 T-type channels, chromosome 7q22-31 region; neuroligin-4 missense mutation; ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1, VMAT1; SLC18A1, microcephalin 1 gene (MCPH1).

Genetic polymorphisms of cytochrome P450 enzymes, 2p15-16.1, neurobeachin (Nbea); rs1858830 C allele variant, 3q26.31, serotonin receptor 2A gene (HTR2A); 1q42 deletion involving DISC1, DISC2, and TSNAX; alpha4beta 2 nicotinic acetylcholine receptors, adenosine A(2A) receptor gene (ADORA2A) variants; chromosome 1p34.2p34.3, synaptic vesicle gene RIMS3; microdeletions at 17q21.31, linkage loci on chromosomes 7 and 2; 2q37.3 deletion, neuroligin-3 R451C mutation; 2q24-2q31, 7q, 17q11-17q21; synaptic genes NLGN3, NLGN4, and CNTNAP2; dysfunctional ERK and PI3K signaling, ribosomal protein L10 (RPL10) gene, glutamate decarboxylase gene 1 (GAD1) located within chromosome 2q31.

Breakpoints on chromosomes 5 and 18; short arm of chromosome 20, chromosome 20p12.2, serotonin receptor genes HTR1B and HTR2C; genes at 3q25-27, deletion of chromosome 2p25.2, chromosome 10, chromosome 1q21.1; Joubert syndrome gene (AHI1), deletion in 6q16.1, including GPR63 and FUT9; duplication of 8p23.1-8p23.2, NLGN4Y gene, inverted duplication of proximal chromosome 14; SYNGAP1, DLGAP2, X-linked DDX53-PTCHD1 locus; interstitial deletion 9q31.2 to q33.1, methyl-CpG binding protein 1; balanced de novo translocation between chromosomes 2 and 9; contactin 4 (CNTN4), chromosome 2q24-q33 region, PAX6 gene; deletion on 18q12, chromosome 5q31, PTEN, 13q21.

Microdeletions at 7q11.23, chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q, 22q; FMR1 protein, FOXP2 gene; 2q35 and 8q21.2 breakpoint, sodium channels SCN1A, SCN2A and SCN3A; paternally derived chromosome 13, somatostatin receptor 5 (SSTR5) on chromosome 16p13.3; terminal 11q deletion and a distal 12q duplication, APOE protein, allelic variants of HOXA1/HOXB1; notch4 gene polymorphisms, AVP receptor 1a (AVPR1a), mitochondrial aspartate/glutamate carrier SLC25A12 gene; Arg451Cys-neuroligin-3 mutation, language loci on chromosomes 2, 7, and 13; de novo translocation t(5;18)(q33.1;q12.1), p11.2p12.2.

Mu-opioid receptor gene, chromosome 16p13.3, trisomy 15q25.2-qter; 14q32.3 deletion, autism loci on 17q and 19p, linkage at 17q11-17q21, linkage on 21q and 7q; 3q29 microdeletion, haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16; 6p25.3-22.3, SLC25A12 and CMYA3 gene variants; chromosome 3q25-27, inversion inv(4)(p12-p15.3), partial trisomy of chromosome 8p; locus in 15q14 region, terminal deletion of 4q, duplication at Xp11.22-p11.23; SEMA5A expression Tachykinin 1 (TAC1) gene SNPs, TPH2 and GLO1; biallelic PRODH mutation, recurrent 10q22-q23 deletions, neuropilin-2 (NRP2) gene polymorphisms.

Yes, I know—it might have taken less space to list the genetic features scientists have not implicated in autism's etiology.

Saturday, June 12, 2010

A Different Perspective on a Likely Mirage

One more thought regarding the report recently published in the journal Nature, Functional impact of global rare copy number variation in autism spectrum disorders (Pinto et al., 2010):

If someone wanted to put forth the hypothesis that rare copy number variation has no causal relationship whatsoever to autism, he would be hard pressed to find a more supportive set of evidence than the data supposedly backing the claims being made in (Pinto et al., 2010). Desperate people often see fantastic visions.

A Futuristic Vision

I can see where this co-authorship thing is heading. One day in the not too distant future a paper will appear entitled Today, consisting of a single sentence: “We did some stuff.” The authorship list will comprise the names of the six billion some human inhabitants of this planet, and the paper will be published in the journal Nature, which seems to have a hankering for these things. Everyone can then go about their business of applying for tenure, comfortable in the knowledge it will not be denied.

I hope that day comes soon; in fact, it cannot arrive fast enough. Because then maybe someone—anyone—will finally feel free enough to develop an idea on his own.

Friday, June 11, 2010

How To Talk Like a Modern Scientist

Humans were once curious as to why certain homes had an address of Toledo, Ohio while most homes did not. Modern scientists, attracted by some sizable grants, decided to look into the matter. Here is what a few of them had to say about their findings:

“We compared furniture arrangements of a large set of Toledo homes versus controls and found that if we focused on unusual furniture arrangements (those found in less than 1% of the homes), we could get some interesting and hopefully publishable results. At first we were disappointed to discover that both Toledo and non-Toledo homes were equally likely to have unusual furniture arrangements, but when we cast our statistical eye further we noticed that for unusual furniture arrangements involving television sets (rare televisionic furniture arrangements), Toledo homes were somewhat more likely to have such arrangements than controls. This is a major breakthrough.”

“We discovered novel candidate furniture arrangements that significantly increase the risk of having a Toledo address. This will allow us to develop home decorative intervention strategies and get furniture therapists to front doors much quicker—in some instances preventing homes from ever appearing in Toledo, Ohio.”

“Our results substantiate the importance of unusual furniture arrangements in Toledo homes, and this is likely to change how home decoration is viewed in the Toledo area. Most people in the field believed that Toledo homes shared common furniture arrangements perhaps in just a few rooms. But in fact most Toledo homes are probably decoratively quite unique—each having their own form of furniture arrangement.”

“You and I may have just as many unusual furniture arrangements in our homes, but since they don't involve television sets, we don't live in Toledo, Ohio.”

“Of great significance to us was the finding that in seven of the Toledo homes there was an unusual furniture arrangement involving a Go Mud Hens pennant, whereas this unusual furniture arrangement did not show up in any of the controls. We double checked against a broad population of Canadian homes and confirmed that those also did not have any Go Mud Hens pennants. This is consistent with earlier findings of high risk Toledo furniture arrangements—such as those involving cheap bowling trophies.”

“The findings, to some extent, are not unexpected. These unusual furniture arrangements are turning up in a number of other cities so it is no surprise that they may be involved in Toledo, Ohio as well. How significant they are will await further testing as to how sensitive and specific these furniture arrangements are as well as what percent of Toledo, Ohio is involved.”

“We have been trying to put together a very large jigsaw puzzle without having the benefit of a nice colorful picture on the box. The unusual furniture arrangements are like the edges, you might say, and they give us an idea of what the picture may look like. With these findings, we are starting to find some of the edge pieces, and that may provide us with some sort of framework for looking at how these decorative schemes work in Toledo, Ohio, leading to cartological features and how these might work in collaboration with the geography, thus producing some of the Toledo houses that we can see around us.”

“The exciting thing about the findings of this study is that it highlights fashionable pathways that can be targets for renovation.”

“Even with these findings, we are able to explain only about 10 percent of the homes in Toledo, Ohio. What causes the other 90 percent of Toledo homes to be located where they are is still on the table. Every little victory is important, but it's still amazing how little we know.”


Questions Unasked

One of the advantages of being an outsider to autism science is that I get to ask simple questions. Take for instance autism's latest hullabaloo, the paper recently published in the journal Nature, Functional impact of global rare copy number variation in autism spectrum disorders (Pinto et al., 2010). There are questions about this study that the media will not ask, nor apparently will any of the study's nearly two hundred authors. I, on the other hand, have no such reservation:

  • If particular types of rare copy number variants (CNVs) are only slightly more likely in autistic individuals than in non-autistic individuals (which is what the study indicates), and if the ratio of autistic individuals to non-autistic individuals is approximately 1:99, then aren't the vast majority of instances of these particular CNVs going to be found within the non-autistic population? And if so, how distinctive for autism can these CNVs possibly be?

  • How is it that only the CNVs which are more likely in autistic individuals can produce significant consequence, whereas the hundreds of other CNVs (from both populations) are apparently benign? Is this science—or wishful thinking?

  • How is it that the broad variety of CNVs more likely in autistic individuals (which are apparently the only ones that can produce significant consequence)—how is it that this diverse hodge-podge of CNVs can all lead to the same diagnosable condition? Is this science—or an amazing coincidence?

  • If the purpose of this study was to uncover a genetic signature underlying autism, shouldn't the major conclusion of this study be that there isn't one?

There are reasons that simple questions go unasked, but those reasons seldom have anything to do with the actual results. I have heard the spin being placed on this study in the media, and I have also listened to what the study's authors have had to say, but I can tell you without hesitation that the study's raw data imparts an entirely different story. Let me put it this way: if you are one of the nearly two hundred scientists who has managed to finagle your name onto the authorship list, then the publication of this study is a positive result; otherwise, it is a whole bunch of nothing.

Wednesday, June 9, 2010

The Unique Accomplishment of Laurent Mottron

I have written previously on this blog about the many innovative and original contributions made by Laurent Mottron and the members of his autism research team, but it would appear this time Dr. Mottron has gone and completely outdone himself in the new paper appearing in the journal Nature, Functional impact of global rare copy number variation in autism spectrum disorders (Dalila Pinto, Alistair T. Pagnamenta, Lambertus Klei, Richard Anney, Daniele Merico, Regina Regan, Judith Conroy, Tiago R. Magalhaes, Catarina Correia, Brett S. Abrahams, Joana Almeida, Elena Bacchelli, Gary D. Bader, Anthony J. Bailey, Gillian Baird, Agatino Battaglia, Tom Berney, Nadia Bolshakova, Sven Bolte, Patrick F. Bolton, Thomas Bourgeron, Sean Brennan, Jessica Brian, Susan E. Bryson, Andrew R. Carson, Guillermo Casallo, Jillian Casey, Brian H.Y. Chung, Lynne Cochrane, Christina Corsello, Emily L. Crawford, Andrew Crossett, Cheryl Cytrynbaum, Geraldine Dawson, Maretha de Jonge, Richard Delorme, Irene Drmic, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Eric Fombonne, Christine M. Freitag, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Jeremy Goldberg, Andrew Green, Jonathan Green, Stephen J. Guter, Hakon Hakonarson, Elizabeth A. Heron, Matthew Hill, Richard Holt, Jennifer L. Howe, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Olena Korvatska, Vlad Kustanovich, Clara M. Lajonchere, Janine A. Lamb, Magdalena Laskawiec, Marion Leboyer, Ann Le Couteur, Bennett L. Leventhal, Anath C. Lionel, Xiao-Qing Liu, Catherine Lord, Linda Lotspeich, Sabata C. Lund, Elena Maestrini, William Mahoney, Carine Mantoulan, Christian R. Marshall, Helen McConachie, Christopher J. McDougle, Jane McGrath, William M. McMahon, Alison Merikangas, Ohsuke Migita, Nancy J. Minshew, Ghazala K. Mirza, Jeff Munson, Stanley F. Nelson, Carolyn Noakes, Abdul Noor, Gudrun Nygren, Guiomar Oliveira, Katerina Papanikolaou, Jeremy R. Parr, Barbara Parrini, Tara Paton, Andrew Pickles, Marion Pilorge, Joseph Piven, Chris P. Ponting, David J. Posey, Annemarie Poustka, Fritz Poustka, Aparna Prasad, Jiannis Ragoussis, Katy Renshaw, Jessica Rickaby, Wendy Roberts, Kathryn Roeder, Bernadette Roge, Michael L. Rutter, Laura J. Bierut, John P. Rice, Jeff Salt, Katherine Sansom, Daisuke Sato, Ricardo Segurado, Ana F. Sequeira, Lili Senman, Naisha Shah, Val C. Sheffield, Latha Soorya, Ines Sousa, Olaf Stein, Nuala Sykes, Vera Stoppioni, Christina Strawbridge, Raffaella Tancredi, Katherine Tansey, Bhooma Thiruvahindrapduram, Ann P. Thompson, Susanne Thomson, Ana Tryfon, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, Simon Wallace, Kai Wang, Zhouzhi Wang, Thomas H. Wassink, Caleb Webber, Rosanna Weksberg, Kirsty Wing, Kerstin Wittemeyer, Shawn Wood, Jing Wu, Brian L. Yaspan, Danielle Zurawiecki, Lonnie Zwaigenbaum, Joseph D. Buxbaum, Rita M. Cantor, Edwin H. Cook, Hilary Coon, Michael L. Cuccaro, Bernie Devlin, Sean Ennis, Louise Gallagher, Daniel H. Geschwind, Michael Gill, Jonathan L. Haines, Joachim Hallmayer, Judith Miller, Anthony P. Monaco, John I. Nurnberger Jr, Andrew D. Paterson, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Peter Szatmari, Astrid M. Vicente, Veronica J. Vieland, Ellen M. Wijsman, Stephen W. Scherer, James S. Sutcliffe and Catalina Betancur, 2010).

There you can see it for yourself, in plain black and white, defying what must have been nearly insurmountable odds—Laurent Mottron has somehow managed to get himself not included in the list of contributing authors. What else can I say—this is clearly a unique accomplishment within the current field of autism research.

Indeed, Dr. Mottron's feat is so unusual and amazing that it leaves me wondering how he possibly could have pulled it off. My suspicion is that Geraldine Dawson, panicked at the thought of perhaps being excluded from the authorship list (which would itself be a unique and amazing event), during her mad, entreating rush to track down the head author must have knocked Dr. Mottron over and rendered him totally unconscious for a considerable period of time, thus leading to his name not appearing on the roll. But little matter. In an accomplishment like this—where one has so definitively set himself apart from all his peers—the means are merely a secondary consideration, the accomplishment is the thing. My heartiest congratulations!

Sunday, June 6, 2010

Memetic Residue

Can we assume that Richard Dawkins has plunged headlong (and superciliously) into his anti-religion career mostly because the biology gig did not work out?

Bright Dissent

I was thinking of fostering an Atheists Against Richard Dawkins movement, but unfortunately, its first commandment would have to be, “Thou shalt not be so fatuous as to foster a movement.”