Genetics

Copies count

Some genes have more than one copy, and the copy number can differ among individuals. But does this variation affect the person involved? It seems susceptibility to certain common diseases can be altered.

Each of our kidneys consists of about one million glomeruli — clusters of tiny blood vessels that together filter a remarkable 50 gallons of blood each day. Filtering separates waste products for excretion while retaining water and other vital substances such as glucose and proteins. In diseases such as diabetes and systemic lupus erythematosus (SLE), inflammation causes progressive loss of filtering abilities, leading to a condition known as glomerulonephritis that often results in kidney failure and renal disease. As with any disease caused by a combination of environmental and multiple genetic factors, tracking down the individual genetic components of glomerulonephritis has been a daunting task. In this issue, Aitman et al.1 (page 851) provide compelling evidence that differences in the number and nature of a gene called Fcgr3 contribute to the development and progression of the disease in rat models and humans. Their discovery suggests that copy-number variation, which is a major source of genetic variation in humans and other species, may contribute to susceptibility to other common diseases.

Despite the complications that result from the multigenic control of disease susceptibilities, the genes that contribute to common diseases such as heart disease are beginning to be identified2. Examples in humans include the genes that contribute to asthma3, and to myocardial infarction and stroke4. In mice, certain genes have been implicated in age-related sensorineural hearing loss5 and susceptibility to atherosclerosis6. And several rat genes have been linked to unresponsiveness to insulin and to diabetes7. The Fcgr3 gene is the most recent addition to the list of identified complex trait genes. Genes typically affect an individual's susceptibility to a disease because mutations change either the amount or the composition of the protein encoded by the gene. But in the case of Fcgr3 in glomerulonephritis, the underlying molecular alteration is simply a change in the number of copies of the gene.

Aitman and colleagues' discovery1 came from work on the Wistar Kyoto (WKY) rat strain, which is a model for glomerulonephritis in humans. Ten days after injection with a toxic serum8, these rats develop nephrotoxic nephritis, which has many pathological similarities to certain forms of human glomerulonephritis. By contrast, other rat strains such as the Lewis and Brown Norway strains do not succumb to the disease after the injection.

By breeding susceptible strains with resistant ones, Aitman et al. surveyed the rat genome for genes that are associated with nephrotoxic nephritis, and identified two important regions — one on chromosome 13 and the other on chromosome 16. The one on chromosome 13 is near a family of genes encoding receptors involved in immune responses, including Fcgr3. The authors found that WKY rats and other susceptible strains have only a single copy of the Fcgr3 gene. But resistant strains including Lewis rats have a copy of the Fcgr3 gene and a copy of the Fcgr3-related sequence (Fcgr3-rs), which probably evolved from a duplication of the Fcgr3 gene (Fig. 1).

Figure 1: Organization of the Fcgr3 genes in Lewis and WKY rats.
figure1

Chromosome 13 in Lewis rats has one copy of the Fcgr3 gene and one copy of the related gene Fcgr3-rs. In WKY rats, the same chromosome contains only the one Fcgr3 gene. Fcgr3 in both strains has an extra 226 base pairs, including a so-called SINE element. The Fcgr3-rs gene in Lewis rats has a single nucleotide deleted (ΔG129). Aitman et al.1 show that loss of the Fcgr3-rs gene in WKY rats contributes to susceptibility to nephrotoxic nephritis, a disease that recapitulates certain types of human glomerulonephritis.

The Fcgr3 and Fcgr3-rs genes in the rat have two differences. First, Fcgr3 has an extra 226 base pairs inserted into the so-called 3′-untranslated region, which may regulate the amount of encoded protein expressed but doesn't affect the protein itself. The second difference involves the loss of a single nucleotide in the Fcgr3-rs gene (ΔG129) that alters the composition of the encoded receptor protein: the deletion results in a cytoplasmic domain in the protein that is longer by six amino acids.

The Fcgr3 gene encodes a transmembrane receptor that is found on certain immune cells, including macrophages, and is involved in the inflammatory response. Activation of the receptor causes the immune cells to kill neighbouring non-immune cells, either by engulfing them (phagocytosis) or by producing antibodies that kill them (cytotoxicity). Macrophages from the WKY rats produced greater cytotoxicity than macrophages from the Lewis rats. Moreover, adding Fcgr3, Fcgr3-rs or a variant of Fcgr3 with the ΔG129 deletion to cells in culture can alter their behaviour. Cells with Fcgr3 alone had higher levels of phagocytosis than those with Fcgr3-rs or Fcgr3-ΔG129. However, adding Fcgr3-rs to the Fcgr3 cells inhibited phagocytosis, implying that Fcgr3-rs damps down the effects of Fcgr3. So when Fcgr3 is lost in WKY rats, the macrophages become hyperactive. Together, the genetic and functional evidence satisfies the requirements of proof needed to establish that a genetic variant contributes to a complex multifactor trait2.

But how does this relate to humans? Aitman et al. examined the FCGR3B gene (the human relative of Fcgr3) in individuals with glomerulonephritis associated with SLE. The inheritance patterns of this gene in some families affected by SLE had suggested that copy-number variation might underlie the condition. The authors found that from none to four copies of FCGR3B can exist in a cell, but this number is lower among SLE patients with glomerulonephritis than in unaffected control individuals. This indicates that reduced FCGR3B copy number is a risk factor for glomerulonephritis in SLE patients.

Copy-number variation is a major type of genetic variation among humans9,10, and among inbred strains of mice11,12. Currently, 1,237 copy-number variations have been identified13. Many of these occur in regions with large repeated or duplicated segments, which may increase the propensity for the DNA rearrangements that cause copy-number variations14. The functional attributes of proteins encoded by number-variant genes show that there is an enrichment for genes involved in drug detoxification, the immune response and inflammation, cell-surface integrity and cell-surface antigens15.

So, copy-number variants may well contribute significantly to the inter-individual variation seen in responses to drugs, immune defence and susceptibility to certain diseases. These variants could enhance or ameliorate many disease symptoms — as in the case of Fcgr3 and glomerulonephritis, which is an often devastating complication of several common diseases. It is now possible to explore the functions of Fcgr3 in the kidney, and perhaps to identify the naturally occurring agents that elicit the immune response leading to compromised kidney function in Fcgr3 variants. Equally, it will be exciting to see what future discoveries will associate gene-copy-number variants with other common human diseases and their animal models16.

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