Human MutationIN THIS ISSUE

& One of the Reasons Why Humans, andnot Sponges or Worms, get PsychiatricDisorders?

Alas, classical genetics again has insulted my sense of humangenomic superiority. August 2010 saw the publication of thegenome sequence of the demosponge, A. queenslandica (Srivas-tava, Nature 466:720– 726, 2010), the ancestors of which wereamong the first forms of multicellular life. It has 418,000 genes,roughly the same number as C. elegans, which has only 959 cells.The insult is, of course, that humans only have a few thousandmore classical protein-coding (CDS) genes than a sponge, or aworm with only 302 neurons!

So why are we more complex ‘‘higher organisms’’ prone todevastating psychiatric disorders (PDs) such as bipolar disorderand schizophrenia, which we know have a strong geneticcomponent? In this issue, Forero et al. (Hum. Mutat.31:1195– 1204, 2010) note that, for many PDs, the most highlyassociated SNPs (with low odds ratios) in replicated and non-replicated genome-wide association studies are non-CDS andintergenic. Part of the answer came with the discoveries of smallinterfering RNAs (siRNAs) in C. elegans and micro RNAs(miRNAs), non-coding RNAs (ncRNAs) which can have directeffects on regulation of coding gene expression through mRNAstability or translation. The larger the genome is and the more‘‘junk’’ it appears to contain compared with that of a sponge or aworm, there is a corresponding increase in the transcription of arange of ncRNAs from intergenic and even intragenic regions(Mattick, J. Exp. Biol. 210:1526– 1547, 2007). Importantly,miRNAs are known to target mRNAs for key developmentalmolecules during brain development.

There is an increasing catalogue of dysregulated miRNAexpression in PD patient samples and genetic association withmiRNA sequence variation. So, as discussed by Forero et al., is itthe cumulative biological effects of rare sequence variants inmiRNAs, their 30-untranslated region targets, and other ncRNAs,that are partially the cause of PDs? Sponges and worms don’t havethe genetic and genomic complexity to produce the numeroussequence variants, miRNAs, and other ncRNAs to have ourcellular and neuronal complexity and thus get PDs. So in a way,I’m both less genetically insulted but more genetically depressed.

–Hamish S. Scott, University of AdelaideDOI 10.1002/humu.21380

& Expanded Carrier Screening in theAshkenazi Jewish Population

In the past, carrier screening for autosomal recessive diseaseshas focused on relatively frequent, severe, childhood disorders thathave a high detection rate. As a result of the Human GenomeProject, the ability to detect carriers of most autosomal recessivediseases will soon become a reality. The question will be whichdiseases to screen and which criteria are used to make thesedecisions. In this issue, Scott et al. (Hum Mutat 31:1240– 1250,2010) describe their experience testing for 16 autosomal recessiveconditions. This represents a significant expansion to the panelthat has been suggested by the American College of Obstetriciansand Gynecologists (ACOG) and the American College of MedicalGenetics (ACMG), and as such the article could inspire somediscussion on the topic.

The authors present important data on the carrier frequenciesin a large Ashkenazi Jewish (AJ) population for these 16 diseases.Furthermore, they postulate on the future of screening and howthe landscape of carrier screening may be significantly altered withnew technology to be more inclusive. It is the latter point thatneeds to be addressed. Already, some of the diseases in theirexpanded panel have characteristics that differ from thosetraditionally included in screening programs: diseases that arerare (e.g., nemaline myopathy), are clinically variable (e.g.,Gaucher, lipoamide dehydrogenase), and have less than idealdetection rates (70% for Usher 1F).

Do we need more data before offering to screen for diseasessuch as these? Scott et al. conclude that ‘‘AJ parents want to test forall the possible debilitating/neurodegenerative disorders.’’ Thisassumption is based on data that less than 5% opted out of the fullpanel. A dialogue is necessary to probe both genetic professionalsand the population at risk for which criteria should be used whenconsidering expansion of these programs. Could we avoid undueanxiety and potentially risky procedures like amniocentesis bygathering this knowledge? Perhaps we need to look before we leap.

–John Mitchell, McGill University Health CentreDOI 10.1002/humu.21381

OFFICIAL JOURNAL

www.hgvs.org

& 2010 WILEY-LISS, INC.