Gene variations and diseases – far from simple

The genome of an individual normally exhibits variations from the reference human genome identified by the Human Genome Project.  Some of these variations are inherited, some are due to mutations, some may be harmful, some are beneficial and some may indicate disease susceptibilities. 

The most familiar kinds of gene variations are SNPs, single-nucleotide polymorphisms,” a variation occurring when a single nucleotideA, T, C, or G — in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual(ref).  Another kind of variation of increasing interest is a CNV, a copy number variation, meaning a missing sequence of DNA, incorrectly-inserted DNA or too many copies of a given DNA sequence.  

SNPs and CNVs occur much more commonly than once thought and are not necessarily harmful.  A 2006 study of 270 individuals revealed an average of 47 CNVs per person(ref).  More-recent research indicates that there may be as many as 1,000 CNVs in the average person(ref).

Defects in some individual genes are known to confer specific disease susceptibilities, perhaps the best known of these being BRCA1 and BRCA2, tumor suppressor genes.   Mutations of these are linked to hereditary breast and ovarian cancer(ref).  Another example is cystic fibrosis which is associated with a mutation in (or two copies of) the CFTR gene(ref). Down’s Syndrome is caused by a CNV in which an extra copy of chromosome 2, in whole or in part, is inherited.

In some cases gene families are known to indicate increased disease susceptibility, for example as recently reported for non-Hodgkin lymphoma: “Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted(ref).”

In most cases the relationships between genetic variations and specific diseases are complex, probabilistic and still being explored.  Only rarely is there the situation “one bad gene, one disease.” For example, for a recent study relating bladder cancer to SNPs it is reported(ref):  “These authors evaluated the role of single nucleotide polymorphisms (SNPs) and bladder cancer risk and case survival. The authors used a panel of SNPs in potential cancer regulatory pathways, including cell cycle, cell growth, detoxification, telomerase, and apoptosis. They ranked causative or survival-associated single gene and multi-gene-combinations using a large, population-based case-control study in New Hampshire, USA. There were 832 cancer patients and 1,191 controls. The vast majority had non-invasive bladder cancer. 1,421 SNPs were evaluated, representing 400 cancer related genes. Bladder cancer risk was associated with altered genes in detoxification (GSTZ1_02 and pG42R), PAH metabolism (AKR1C3_35), pigmentation (TYR_02), lipid metabolism (SCARB1_03), and metabolism (SLC23A1_05). Altered genes associated with bladder cancer survival included surface antigens (CD80_04), apoptosis (BCL2L1_03 and CASP9), detoxification (EPHX1_15), and DNA repair (ERCC4_01)(ref). “A single-nucleotide polymorphism (SNP, pronounced snip) is a DNA sequence variation occurring when a single nucleotideA, T, C, or G — in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual)(ref).

The situation with respect to schizophrenia and bipolar disease is even more complex.  According to news reports this week: “Researchers at Stanford and 14 other institutions carried out a study of common DNA variations throughout the genome, and then combined forces with two independent studies to complete a pooled analysis of 27,000 individuals. The largest genetic differences between the study participants with and without schizophrenia were found on a stretch of chromosome 6 containing numerous genes associated with immune response (and some with other roles). This raises the possibility that immune function plays a role schizophrenia(ref).” The three studies found 30,000 common gene variations linked with the mental illness(ref).” While the research appears to be solid, the researchers are still far from being able to relate susceptibility to schizophrenia or bipolar disease to gene variation patterns.

Discoveries are coming at a fast pace and there are many tantalizing clues.  For example a 20 kilobase deletion CNV upstream of the IRGM gene is known to contribute to Crohn’s disease susceptibility according to a multi-species study(ref)(ref).  CNVs are associated with bone density based on a study of 6,865 Icelanders 8,510 subjects of European descent (ref).  CNVs at seven loci are identified with obesity(ref).  And here in one issue of Nature Genetics are reports of other studies relating CNVs to coronary heart disease risk, polygenic dyslipidemia, body mass index, type 2 diabetes, sclerosing skeletal dysplasia, and reticular dysgenesis.

  There is a great deal of ongoing research focused in linking SNP and CNV variation patterns with diseases such as is described here, and multiple  SNP and CNV databases are being built.  Because of the complexity, discovering disease relationships may be increasingly a task of applying computational genomics to databases.  See this listing of medical genetics databases. I expect there will be a lot more to report about this topic as time progresses.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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