Scientists Narrow Search for Genes that Control the Breathing Response

Researchers at the Johns Hopkins School of Public Health have taken a significant step toward identifying the genetic basis for the hypoxic ventilatory response -- how a person's breathing apparatus reacts to an oxygen-poor (hypoxic) environment. Working with mice, the researchers were able to generate a model in which the genetic components of breathing were simplified, to focus on two or three likely genes that might control hypoxic breathing. The study appeared in the June 2000 issue of the Journal of Applied Physiology.

Scientists have long known that individual human responses to an oxygen-poor environment vary six- to seven-fold in sensitivity, but that these widely varying breathing patterns cause no problems in healthy individuals. Among patients with lung disorders, however, those with low sensitivity to hypoxia have significantly greater morbidity and risk of mortality. Thus, people with asthma, obesity, or sleep apnea, as well as babies at risk for sudden-infant death syndrome (SIDS), could all potentially benefit from the identification of the genes controlling hypoxic breathing.

Lead author Clarke G. Tankersley, PhD, MSc, assistant professor of physiology in the Department of Environmental Health Sciences, the Johns Hopkins School of Public Health, said, "We're in the process of locating in mice some of the genes that control breathing and that have the best potential for directing the search for corresponding genes in humans."

The researchers turned to two inbred strains of mice -- the C3 and the B6 strains -- to identify breathing patterns that were obviously inherited. Since all mice within the same inbred strain are genetically identical, and since the environment in the laboratory could be carefully maintained, any variations detected in the hypoxic breathing patterns of these strains would most likely be genetic. (Unlike mice, humans obviously cannot be inbred, and so the human genome is much too diverse and varied to allow researchers easy access to the genetic constituents of breathing.)

The study demonstrated three different profiles of hypoxic ventilation among the C3 and B6 strains and their offspring. At baseline, the C3 mice demonstrated a slow, deep breathing pattern, whereas the B6 strain had a much more rapid and shallow breathing pattern. These differences in the baseline breathing patterns of the two mouse strains were preserved when the C3 and B6 mice were exposed to oxygen-poor air.

The responses to low oxygen levels by the first generation offspring, however, were significantly blunted and reduced compared to the parent strains. This blunted hypoxic ventilatory response in the offspring suggested that not any one gene, but a combination of genes derived from the parental strains, conferred susceptibility to breathing problems.

After gathering data on the volume and frequency of breathing of these two mouse strains, as well as of their offspring, the researchers could see clearly that the traits were inherited. They then used a statistical method to evaluate the distributions of these three distinct breathing patterns among parent mice and offspring, to gain a clearer picture of the genes involved.

The investigators next plan to examine the DNA of second-generation mice, looking for major genes that correlate with the ventilatory characteristics of the parent mice. Such genetic combinations in mice will suggest possible sites along the human genome where genes controlling hypoxic breathing may be located.

Are the investigators ready to implicate any particular genes as the cause of hypoxic breathing? "At this point," said Dr. Tankersley, "I'm still very conservative. I'd like to think we have a couple of genes in mind, but it would be irresponsible at this point to consider those possibilities before our peers have reviewed our results."

This study was supported by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medical Sciences; and the National Institute of Environmental Health Sciences Center at the Johns Hopkins School of Public Health; as well as by a Public Health Service Resource Grant from the National Center for Research Resources.