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Departments of 1 Environmental Health Sciences and 2 Anesthesiology, The Johns Hopkins University, Baltimore, Maryland 21205
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Tankersley, Clarke G., Robert S. Fitzgerald, Roy C. Levitt,
Wayne A. Mitzner, Susan L. Ewart, and Steven R. Kleeberger. Genetic control of differential baseline breathing pattern. J. Appl. Physiol. 82(3): 874-881, 1997.
The purpose of the present study was to determine the genetic
control of baseline breathing pattern by examining the mode of
inheritance between two inbred murine strains with differential
breathing characteristics. Specifically, the rapid, shallow phenotype
of the C57BL/6J (B6) strain is consistently distinct from the
slow, deep phenotype of the C3H/HeJ (C3) strain. The response
distributions of segregant and nonsegregant progeny were compared with
the two progenitor strains to determine the mode of inheritance for
each ventilatory characteristic. The BXH recombinant inbred (RI)
strains derived from the B6 and C3 progenitors were examined to
establish strain distribution patterns for each ventilatory trait. To
establish the mode of inheritance, baseline breathing frequency (f),
tidal volume, and inspiratory time
(TI) were measured five times
in each of 178 mature male animals from the two progenitor strains and
their progeny by using whole body plethysmography. With respect to f
and TI, the two progenitor strains were consistently distinct, and segregation analyses of the
inheritance pattern suggest that the most parsimonious genetic model
for response distributions of f and
TI is a two-loci model. In
similar experiments conducted on 82 mature male animals from 12 BXH RI
strains, each parental phenotype was represented by one or more of the
RI strains. Intermediate phenotypes emerged to confirm the likelihood
that parental strain differences in f and
TI were determined by more than
one locus. Taken together, these studies suggest that the phenotypic
difference in baseline respiratory timing between male B6 and C3 mice
is best explained by a genetic model that considers at least two loci
as major determinants.
inbred mice; control of ventilation; respiratory timing; breathing
frequency; BXH recombinant inbred strains
INTRODUCTION QUETELET WAS AMONG the first to report the baseline
breathing frequency (f) of normal healthy human subjects and to
articulate the conditions (e.g., age, gender, wakefulness) that cause
variation in respiratory rate (21). Since then many studies have
investigated the neural and mechanical processes that control f (e.g.,
Refs. 18, 19) and have defined conditions that modify these mechanisms. Generally, central neural modulation initiates the generation of the
breathing rhythm, whereas peripheral pulmonary stretch receptors
delineate the timing of the inspiratory phase of each tidal breath (2,
13, 26). Another principle central to the control of f is the notion
that optimal respiratory pattern is regulated to maximize both
breathing efficiency in terms of mechanical cost as well as alveolar
ventilation to facilitate gas exchange (19). A number of studies (e.g.,
Refs. 1, 5) have demonstrated relationships between predicted and
observed optimal breathing frequencies among many mammalian species
including mice and humans. Although many advances have been made since
Quetelet (21) to improve our understanding of the complex interaction among neural, mechanical, and other factors that control baseline f,
little attention has been given to the contribution of genetic determinants.
Recently, Tankersley et al. (29) described significant variation among
eight inbred strains of mice with respect to baseline f. The
variability observed between these strains was significantly greater
than within each strain, suggesting that genetic determinants account
for a significant proportion of variation in f. The general purpose of
the present study was to examine more closely the role of genetic
constituents in controlling baseline breathing pattern and respiratory
timing. Two inbred strains, which were phenotypically distinct with
respect to baseline breathing characteristics, were used to determine
the mechanism of genetic regulation of baseline f. If the data support
this hypothesis in mice, we propose that the genetic regulation of
breathing may be determined by similar mechanisms in humans (8, 24).
Two inbred strains, namely, C57BL/6J (B6) and C3H/HeJ (C3),
demonstrate consistent and distinctively diverse breathing patterns while animals are unanesthetized and unrestrained (29). Specifically, the B6 strain adopts a rapid, shallow breathing pattern relative to the
slow, deep pattern characteristic of the C3 strain. This phenotypic
variation in f and tidal volume
(VT) observed between strains
occurs without significant differences in minute ventilation. In the
present study, we sought to determine the best fitting genetic model to
explain the response distributions of the two progenitor strains and
their nonsegregant (i.e.,
B6C3F1) and segregant (i.e., the
two backcross and intercross;
B6C3F2) progeny. In addition, recombinant inbred (RI) strains derived from B6 and C3 progenitors (i.e., BXH RI) were examined to further support the enumeration of loci
controlling strain differences in baseline breathing pattern (25, 28,
31).
METHODS
300 ml/min. After
the animal became quiescent, f,
VT, and inspiratory time
(TI) were recorded on a
strip-chart recorder (model 7D polygraph, Grass). At a constant chamber
volume, changes in pressure due to inspiratory and expiratory
temperature fluctuations were measured by using a differential pressure
transducer (model 8510B-2, Endevco). The inspired air was analyzed for
O2 and
CO2 by a mass spectrometer (model
1100, Perkin Elmer) before and after each ventilatory measurement and
was maintained within 1% of normal room air conditions. Each animal
was weighed after this protocol.
Data acquisition.
The analog signal generated from the pressure transducer was also
recorded as a digital input by using a data-acquisition system
(Keithley Instruments) and a dedicated computer. Data were acquired at
an input frequency of 100 Hz, and peak inspiration and expiration were
determined from 15 consecutive tidal breaths. On the rare occasion
during which data were not secured by computer f,
VT, and
TI were estimated from four
tidal breaths within a 6-s strip-chart recording, as described
elsewhere (29). Least squares regression analysis was used to compare
the two methods of acquiring ventilatory data, and suitable
reproducibility
(r2 = 0.99) was
established for each ventilatory measurement. Pressure transducer
calibrations were performed daily by using a 50-µl gastight syringe
while chamber temperature was maintained similar to the experimental
ambient conditions.
In computation of VT, the
amplitude of the inspiratory and expiratory limbs of each tidal breath
was averaged, and body temperature of each animal was assumed to be
constant at 37°C. Although it is unknown whether strain differences
exist in resting body temperature among the B6 and C3 strains, their
progeny, and the BXH RI strains, variations of 1-2°C in body
temperature account for <5% error in computing baseline
VT. Minute ventilation
(
E) was
calculated as the product of f and
VT. Expiratory time
(TE) was determined from total
respiratory time (TT) minus
TI, mean inspiratory flow was
calculated as the ratio of VT to
TI
(VT/TI),
and the duty cycle was computed as the ratio of
TI to
TT
(TI/TT).
In exploratory studies, the respiratory timing was verified by
positioning a strain gauge on the lateral aspect of the chest wall in
anesthetized mice and assessing the minimum and maximum excursions of
the analog signal generated by the strain gauge. These experiments
demonstrated that the moment of end inspiration and end expiration
during baseline and challenged breathing coincided with the maximum and
minimum excursions of the chest wall, respectively.
Data analysis.
For each individual animal, ventilatory data reported in Figs. 1, 2, 3
represent the average of five repeated measurements. The statistical
procedures were initiated by examining the variance among the
progenitors and their progeny by a one-way analysis of variance. Means
comparisons were performed to test for statistical differences between
each offspring class and the progenitor strains by using Duncan's
multiple-range test and were considered significant at the 
-level of
0.01. Genetic statistical procedures regarding segregation analyses and
the use of RI strains are described in the Appendix.
RESULTS
E and the respiratory duty
cycle (i.e.,
TI/TT).
In contrast, baseline f, VT,
TI,
TE, and mean inspiratory flow
(i.e., VT/TI)
were significantly (P < 0.01)
different between the strains. There was no overlap between the
progenitor strains in the range of responses for f and
TI. For the other ventilatory
traits, the response distributions of the progenitors could not be
consistently classified as typical of either progenitor.
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E, and
TI/TT
were comparable among the progenitor strains and their progeny,
although there were several significant
(P < 0.01) mean differences. The breathing pattern of the F1
progeny was significantly (P < 0.01) different from that of the C3 progenitor with respect to f,
VT, TI, and
TE, and significantly
(P < 0.01) different from the B6 progenitor in terms of VT,
TI,
TI/TT,
and
VT/TI.
With the exception of baseline f, these data suggest that the majority
of ventilatory characteristics for the
F1 progeny differed when compared
with both the B6 or C3 progenitors. A parallel response appeared to exist between the F1 progeny and
the B6 progenitor for baseline f (Fig. 1).
If the rapid breathing phenotype is qualitatively defined based on the
"upper limit" of the C3 response distribution (i.e., 
2.05 Hz in
Fig. 1), the distributions of all individual responses for the
F1 and BXB6 strains were not
different from those of the B6 strain. The individual responses of the
BXC3 progeny were divided into rapid and slow phenotypes, and a ratio
of 14:6 was not significantly different from a 50:50 proportion
predictive of Mendelian inheritance
(
2 = 3.20;
P > 0.05). The response distribution
of the F2 progeny was divided into
rapid and slow phenotypes in a ratio of 57:12, which was not
significantly different from a 75:25 proportion (2 = 2.13;
P > 0.05).
As shown in Fig. 2, the response
distributions of two progenitor strains for baseline
TI were distinct, yet
intermediate phenotypes were demonstrated in each segregant and
nonsegregant population. More specifically, the
TI response distributions for
each offspring class were significantly
(P < 0.01) different from both the
B6 and C3 progenitor strains (Table 1). Because intermediate phenotypes were detected among the segregant and nonsegregant progeny for baseline
TI, the response distributions
did not conform to the proportions predictive of Mendelian inheritance.
The consequence of a greater TI
response for each offspring class relative to the B6 progenitor
accounted for a significantly (P < 0.01) attenuated mean inspiratory flow (i.e.,
VT/TI)
in the groups of progeny compared with that in parental B6 mice.
Statistic Analysis of Genetic Epidemiology (SAGE).
To test a single-gene hypothesis more rigorously, quantitative genetic
models were considered (see Appendix
regarding segregation analysis). One-locus, mixed-loci, and polygenic
general models were rejected in the segregation analysis of baseline f
because the likelihood values associated with these models differed
significantly from the unrestricted model based on the
2 goodness-of-fit test (Table
2). Only the two-loci model did not
demonstrate a significant (P > 0.05)
difference from the unrestricted model. This indicated that the
observed response distributions for baseline f were not significantly
different from expected criteria defining two-loci models. With the use
of Akaike's information criterion (AIC), the most parsimonious model
for baseline f appeared to be the two equal- and additive-loci model.
In a similar way, the segregation analysis for baseline
TI rejected the one-locus, mixed-loci, and polygenic general models; that is, the general two-loci
model was not significantly (P > 0.05) different from the unrestricted model (Table 2).
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E, and
TI/TT.
With respect to f, VT,
TI, and
TE, the responses for the BXH RI
strains encompassed ranges similar to those of the progenitor strains.
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) and 12 BXH RI strains (
) for
breathing frequency and inspiratory time in a cosegregation plot. In a
consideration of 2 baseline breathing characteristics, 3 distinct
phenotypes emerge, with a majority of RI strains favoring B6
phenotype.
DISCUSSION
Although the precise genetic interaction underlying the mechanisms of baseline breathing pattern remains to be elucidated, the simplest genetic model to explain the present results suggests that as few as two genes determine the differences in respiratory timing between male B6 and C3 strains of mice (Table 2). This conclusion is strengthened by the presence of an intermediate phenotype in the BXH RI SDPs, which differed from both the B6 and C3 progenitors (Fig. 4). If the two-gene model proposed in the present study is supported by molecular approaches to mapping of specific genes in the mouse genome, a distinct possibility exists that a limited number of genes are present in the human genome that control differences in individual breathing patterns (8, 24). This hypothesis is based on the high degree of homology between the genomes of the mouse and human species.
Qualitative and quantitative genetic strategies were employed in the present study to enumerate and begin to position the genes determining baseline respiratory timing. These strategies have been used to unravel the genetic control of other complex physiological traits relevant to respiratory physiology (e.g., Refs. 14-16). These studies have led to a broader understanding of the precise molecular basis of the trait in question (e.g., Ref. 6). In the design of the present study, several important controls such as age, weight, and gender were considered. The groups of progenitors, offspring, and RI strains were generally comparable within certain limits; that is, the results of the present study extend to male animals within a 8-16 wk age range. Each animal's baseline breathing characteristics were evaluated in a quiescent state while the animal was unanesthetized and unrestrained. Ventilatory responses were measured five times during intermittent room air exposure within a standard laboratory hypoxic/hypercapnic challenge protocol (29). These measurement criteria were considered an important foundation in assessing the genetic control of baseline breathing characteristics.
We initiated our genetic analyses by using a qualitative approach to test each ventilatory characteristic against a classical Mendelian hypothesis. This requires that the responses of the offspring be classified relative to the parental phenotypes. Under this paradigm, the response distribution for baseline f was the only ventilatory trait that conformed to the proportions predictive of Mendelian inheritance (Fig. 1). Recently, more sophisticated statistical analyses (e.g., SAGE; Ref. 22) permit the evaluation of continuous data by a quantitative genetic approach. Segregation analysis by using SAGE allows one to assess the genetic control of complex traits by considering one-locus, two-loci, mixed-loci, and polygenic models. This strategy was initiated by establishing variance homogeneity and eliminating sources of covariance. For both baseline f and TI, the one-locus, mixed-loci, and polygenic models were rejected by this analysis. These results suggest that the strain differences in baseline f and TI are determined by as few as two genes (Table 2). The development and discovery of many phenotypic and genotypic associations have succeeded in much the same way. Cystic fibrosis, for example, was once thought to be an expression of a single gene mutation but now is believed to be a trait determined by more than one gene (12).
The number of genes can also be estimated by evaluating how the phenotypes of each BXH RI strain compare to the progenitor strains. As shown in Fig. 3, there are four distinct phenotypes for baseline f and three distinct phenotypes for baseline TI. Although the timing of the inspiratory phase is mechanistically linked to the timing of the total respiratory cycle (i.e., the duty cycle is not significantly different among the progenitor and the BXH RI strains, with the exception of BXH 14), the SDPs for these two traits are not altogether qualitatively concordant. This might suggest that, in addition to the two genes that control these traits (as determined by SAGE), other loci may impact on the phenotypic outcome of the baseline ventilatory response. This explanation is supported by the evidence of a fourth phenotype for baseline f (i.e., BXH 14). In Fig. 4, baseline f is depicted as a function of baseline TI in a cosegregation plot. Qualitatively, three distinct phenotypes are apparent, supporting the results from our quantitative analyses that used SAGE. Therefore, a two-loci model appears to be the simplest model to explain a major proportion of the parental strain differences in respiratory timing at baseline.
Presently, it is unknown which mechanisms might result in differences
in baseline respiratory timing between B6 and C3 mice. The f among
groups of mice from the present study were similar to a number of
previous reports (e.g., Refs. 5, 11). Crosfill and Widdicombe (5) and
others (e.g., Refs. 1, 2) suggest that the observed breathing
frequencies of different species are remarkably similar to the optimal
f required to minimize the mechanical work of breathing. These
investigators further suggest that the time constant for mice is very
low relative to other species, which allows for rapid changes in lung
volume; i.e., the optimal f for mice was ~2 Hz (5). From the present
study, the separation in the f phenotypes between the C3 and B6
progenitors occurs between 2.0 and 2.1 Hz (Fig. 1). Likewise, the
response range of f for the entire group of mice examined rarely
exceeded (23 of 260 individuals) the upper or lower limits estimated
for a 10% change in the work of breathing (Ref. 5; Table 1; Fig. 1).
Therefore, it appears that genetic mechanisms that control baseline f
must operate within certain physiological and mechanical constraints
determined by natural selection. The remarkable similarity among the
groups with respect to the baseline
E underscores
this point.
Otis et al. (20) summarized the frequency-dependent mechanical properties of the lung from another theoretical viewpoint. These investigators surmised that pulmonary compliance can be inversely proportional to f because of variation in regional distribution of ventilation and altered regional time constants. In the consideration of those individual animals that exceeded the theoretical upper limit for f (i.e., proposed by Crosfill and Widdicombe; Ref. 5) in the present study, 14 of the 23 individuals originated from three groups, namely, the F1, BXB6, and BXH 14 strains. Coincidentally, the TE was abnormally shortened in these individuals relative to the other groups of mice, suggesting that, if expiration results primarily from passive recoil, the pulmonary compliance of these individuals may be unusually low (2). An alternative explanation might involve strain differences in pulmonary stretch receptors affecting such lung volumes as functional reserve capacity by influencing inspiratory braking mechanisms (13). Although it is difficult to infer strain differences in mechanical properties from the results of the present study, genetic control of structural differences (4, 8, 14, 18) may explain a portion of the respiratory timing variation between progenitor strains.
Differences in lung morphometric parameters have also been described (14) among inbred progenitor strains and their offspring. For instance, the lung volume differences for a given transpulmonary pressure have been illustrated to occur between the B6 and DBA/2J (D2) progenitors. Our laboratory has reported the f of B6 mice to be significantly greater than the D2 strain under similar conditions as the present study (29). This strain difference in breathing pattern was due to a prolonged inspiratory phase and a greater respiratory duty cycle in D2 mice relative to the B6 strain. The B6 and D2 ventilatory data were consistent with the morphometric data and the possible strain differences in compliant properties. On the basis of these associations and the data presented in Table 1, if there were structural differences among the progenitor strains, the C3 mice would hypothetically demonstrate greater lung compliance and lung volume relative to the B6 strain. One strategy to investigate the genetic role of functional and structural interactions between B6 and C3 strains would be to measure individual pressure volume characteristics coincident with variation in baseline breathing pattern among segregant offspring. If the data supported our hypothesis, phenotypic differences in lung compliance would cosegregate with differences in f.
It has long been understood that baseline f is modified by central neurally mediated cholinergic mechanisms. Particularly, conditional variation in f such as state-dependent depression of ventilation has been shown to involve cholinergic mechanisms (17). Recent evidence suggests that the B6 strain is genetically deficient of several cholinergic enzymes including acetylcholinesterase (AChe) in various regions of the brain (e.g., Refs. 3, 23) relative to the D2 strain. It remains controversial whether these biochemical differences accompany strain variation in cholinergic neuronal density. One potential mechanism to explain strain differences in breathing characteristics noted in the present study might involve an AChe deficiency in the B6 strain relative to the C3 strain. This explanation is consistent with the present results, given the hypothesis that the greater f of B6 compared with C3 mice may be related to a lower inhibitory effect of cholinergic stimulation via an AChe deficiency. Furthermore, one might expect that potential strain differences in cholinergic neuronal function may influence the depression in f that occurs with sleep in a strain-specific way. Future studies will be conducted to better understand the extent to which cholinergic mechanisms are involved in regulating strain differences in respiratory timing at baseline.
In summary, the data suggest that polymorphisms in as few as two autosomal genes explain the differences in respiratory timing at baseline between B6 and C3 mice. One hypothesis to test in future studies is the genetic role in establishing strain differences with respect to structural or mechanical properties fundamental to baseline breathing characteristics. Another hypothesis is the genetic control of central neurally mediated cholinergic processes that may determine respiratory timing mechanisms. Ultimately, these studies should lead to a greater understanding of the genetic mechanisms central to the normal breathing characteristics in humans.
ACKNOWLEDGEMENTS
The authors especially recognize the generous contributions of Dr. Benjamin A. Taylor.
FOOTNOTES
Address for reprint requests: C. G. Tankersley, Div. of Physiology, School of Hygiene and Public Health, The Johns Hopkins Univ., 615 N. Wolfe St., Baltimore, MD 21205.
Received 26 February 1996; accepted in final form 22 October 1996.
APPENDIX
Animals
Inbred mice strains are the product of 20 or more generations of brother-sister matings, and within a strain, individuals are genetically identical and homozygotic at essentially all loci (32). As a result of this homozygosity, observed within-strain phenotypic variances may be attributed to environmental factors, whereas the between-strain variance is explained by genetic factors. Thus within-strain variance can be minimized by stringently controlling the environment.Segregation Analysis
The method of Elston (9, 27) was used to estimate the number of genes that segregated with each ventilatory variable. A data-analysis program (CLUSTR; SAGE) (22) was used to estimate group means and variances. The program also identified the transformation parameters that best normalized the data in the genetically homogeneous groups (B6, C3, F1); i.e., the variances of the three groups were made homogeneous. This power transformation (
0.6612 for baseline f; 0.5252 for baseline
TI) was applied to the entire
data set (B6, C3, F1,
F2, and both backcrosses) in
subsequent segregation analyses. The genetic models examined in the
BCROSS program of SAGE (version 2.2, 1994) included one-locus,
two-loci, mixed-loci, and polygenic models (22). Comparisons were made
between each inheritance model and the unrestricted (free) model to
determine whether the restrictions placed on a model significantly
decreased its likelihood. In the segregation-analysis program,
parameters that could be restricted included any of the group means,
common variances, littermate covariances, and the recombination
fraction between two loci. Any restriction placed on a model lowers the maximum likelihood of that model, regardless of the goodness of fit. In
addition to the 2
goodness-of-fit statistic, AIC was used to normalize this reduction in
maximum likelihood across models in which different restrictions were
applied. The AIC was computed by using the number of restrictions placed on a model and the log likelihood of that model as shown in the
following formula AIC = 2 × (log
likelihood no. of restrictions)
BXH RI Strains Analysis
The BXH RI strains are propagated by inbreeding (i.e., brother-sister matings) randomly selected B6C3F2 progeny. After 20 or more generations, BXH RI strains represent stable segregant progeny of the B6 and C3 progenitor strains, and presumably, receive 50% of their autosomal genes from each progenitor strain. On the basis of this property, the phenotypes for any given trait that differ between the progenitor strains are equally likely to be transmitted to any one RI strain. If "new" phenotypes emerge in the RI set (i.e., different from both progenitors), this suggests that more than one locus controls the response (31). Therefore, the BXH RI SDP can be used to estimate the number of loci controlling a particular ventilatory trait (25). The responses of the twelve RI and two progenitor strains were examined by a one-way analysis of variance, and mean comparisons between each RI strain and the two progenitor strains were performed as described above. The BXH RI strains were also used in cosegregation analysis to evaluate phenotypic associations between traits for baseline breathing. If two traits cosegregate in an RI set, this infers that the traits are controlled by common genetic mechanisms.REFERENCES
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