RENEWAL PROPOSAL

MUTATION RATES AND MUTATIONAL LOADS IN MAN

L. L. Cavalli-Sforza

Department of Genetics

Stanford University Medical School
Stanford, California 94305

. Application Date: June 18, 1974

Prepared for the U.S. Atomic Energy Commission, Division of
Biology and Medicine, under Contract Number AT(04-3)-326,
Project Agreement Number 34,

PROM AL

 

“ L. L. Cavalli-Sforza
Professor of Genetics
AEC GRANT RENEWAL

I. Sex Ratio Data

We have received from the Italian Statistical Institute tapes of
the 1962census for the provinces of Siena (central Italy) and
Catanzaro (southern Italy). The study, started in the province of

Verona (northern Italy), will be continued with this new data.

II. Analysis of Parish Book Data

 

The preliminary analysis of inheritance of longevity should be
continued. Further, now that a partially linked file is available
data on fertility and twinning are obtainable and analysis may be

Started on these data.

Itt. Consanguinity

It is hoped that a monograph on Italian consanguineous marriages
will be written by the principal investigator with A. Moroni and others.

Statistical tables for this book are now fully ready:

IV. Human Evolution
a) Ethnic variation. We would like to extend with D. Wagener the
analysis of ethnic variation in genetic disease to dominant diseases.
It is not clear if the numerical data will be found, but a literature
search will be started with this aim in mind.
b) Pygmy demography and effects of acculturation on birth rates.
A new expedition to the Central African Republic is planned with a
purpose to continue studies on the Pygmies. A further reason for this

trip will be to help a group of psychologists headed by Dr. H. Witkin
*.
(Educational Testing Service, Princeton, N.J.). Work on demography

will be continued. Included in this study will be death and birth rates
as well as the change in birth rates which is expected to occur with

the transition to agriculture. As several groups, previously identified,
have effected this transition to agriculture, it is of interest to test
if the expected changes do occur. The budgeted expenses are estimated
for travel between San Francisco and Bangui (capital of the Central

African Republic) and living expenses for one month for one person.
‘
PROPOSED BUDGET

October 1, 1974 to September 30, 1975

Mutation Rates and Mutational Loads in Man

L. L. Cavalli-Sforza
Principal Investigator

PERSONNEL:

L. L. Cavalli-Sforza 10% $ 3,800
Principal Investigator

Albert Ammerman 25% 2,500
(Anthropologist)

Carlo Matessi 50% 6,000
(Geneticist)

4 Graduate Students 10024 2,000
($500 each)

TOTAL SALARIES : 14,300
Staff Benefits (18%)

2,974

TOTAL PERSONNEL $16,874

Computer Time: .
Stanford University 4,000

Travel:
(Foreign) for 1 person
(see IV b) ; 1,500

Publication expenses 500
TOTAL DIRECT COSTS $22,874
Indirect Costs @47% NICD 10,751

TOTAL AMOUNT REQUESTED $33,625
ANNUAL PROGRESS REPORT OF SCIENTIFIC ACTIVITY

FOR PERIOD OCTOBER 1, 1973 through SEPTEMBER 30, 1974

Report Date: June 18, 1974

Mutation Rates and Mutational Loads in Man

L. L. Cavalli-Sforza

Department of Genetics

Stanford University Medical School
Stanford, California 94305

Prepared for the U. S. Atomic Energy Commission, Division of Biology
and Medicine, under Contract Number AT(04-3)-326, Project Agreement

Number 34.
“hy”
Ae

L. L. Cavalli~Sforza

 
AEC PROGRESS REPORT

I. Sex Ratio Data
Data of the 1962 Italian census were analyzed forthe correlation
between the sex ratio of a woman's progeny and the age of the maternal
(and paternal) grandfather at the time of the birth of the woman (G, Zei
and L. Cavalli-Sforza). This correlation was earlier given as a method
of estimating sex linked recessive lethals. Earlier results were contradictory,
The new data from the census of the province of Verona (about one million

people) gave negative results (no correlation). More data will be forthcoming.

II. Analysis of Parish Book Data
A correlation table for the age at death of parents and children of
the Parma Valley project have now become available. These data include
records for three centuries. This is a first major result of the record
linkage project (presently being carried out by M. Skolnick, now of
Utah State University, in collaboration with us and, at Parma, E, Siri
and A. Moroni). There are some fairly weak correlations, weaker than would
have been anticipated from the literature, which is, however, mostly extremely

old, The analysis will require special techniques because of the complicated

distributions of the age at death and their change through time.

‘TIT, Consanguinity

A paper has now been written by Prof. Crumpacker of the University
of Colorado on the subject of the use of road and air distances for the
study of isolation by distance. Consanguineous marriages were also

studied as a function of distance.
IV. Human Evolution

a) Ethnic Variation for Recessive Disease

An analysis of gene frequency data for some recessive diseases was
carried out with D. Wagener to estimate the possible roles of drift, Linkage,
mutation and selection in establishing ethnic variation of these diseases.
Three diseases were used for this study, phenylketonuria (PKU), cystic
fibrosis and Tay-Sachs, for which there is a fair amount of reliable
data encompassing several ethnic groups and which all show considerable
ethnic variation.

To determine the possible role of drift in determining variation, a
solution was obtained for the moments of Wright's distributions of gene
frequencies in populations of size N and mutation rates mu (1). From these
moments the mean gene frequency and Wahlund's variance (a measure of in-
breeding) were determined and compared to the same statistics generated
from observed data. The variation observed for PKU between racial groups
fell within the variation calculated for large populations due to drift.
However, the variation for cystic fibrosis appeared to be relatively higher
than expected. Tay-Sachs, displaying a markedly high variation, was not
entirely explained by this method, but probability of deviations from
the expectations are being calculated to see if this variation is
nevertheless within reason with respect to a drift explanation. We are
not certain that the approximate solution recently offered by Rao and
Morton (2) is satisfactory for a recessive lethal,

Cystic fibrosis, as mentioned above, showed a relatively high racial
variation, This observation coupled with recent reports of an association of

a particular Caucasian Gm haplotype with cystic fibrosis patients
prompted the analysis of non-equilibrium linkage and epistatic models to
generate high variation in gene frequencies. A "hitchhiking model" was
studied in which a deleterious recessive is linked to a locus with an
advantageous allele (e.g. a Gm haplotype). The magnitude and

duration of the increase in the recessive deleterious allele. were
studied. Similar increases, resulting in permanent changes in gene
frequencies, may be generated by unlinked epistatic interactions which
were also studied. This may turn out to be the case for cystic fibrosis
and om.

While this analysis does not rule out possibilities of differences
in mutation or selection rates, it does describe the magnitude of effects
from drift, linkage or epistasis.

b) Analysis of Trees,

Tree analysis of 35 human populations for 58 alleles (including data
from the HL~A Workshop) was carried out by L. Cavalli-Sforza and A. Piazza.
This study provided an occasion for radical reVision of the theory and
methodology. A method borrowed from multivariate analysis can test
“treeness", that is, the existence of a pattern in the matrix of variances
and covariances of populations corresponding to the expected if drift
(random or selection) is important. Constant selection (equal for all
populations) does not affect treeness, However, convergent and divergent
selection will reduce treeness. Hybridization effects can also be clearly
demonstrated by the appropriate analysis. Presently available methods
have been shown to depend on the hypothesis of constant evolutionary
rates, which is frequently wrong; but the methods now developed are free

from such bias. The theoretical and numerical work in this problem has been
‘.

t

time consuming, but the results have been rewarding in our judgment
and two manuscripts, one on the theory and the other on the actual data
analysis, are now almost finished,

c) In a paper presented by Ammerman, et al. to a symposium on
Human Biogeography at the Smithsonian, the work on growth and migration
models of Neolithic populations was summarized. Interpretations of growth
and migration as local events and possible techniques for the recon-

struction of these parameters in specific cases were also discussed.
Research papers resulting from this project:
‘.

Cavalli-Sforza, L. L. 1973. Origin and Differentiation of Human Races

(Huxley Memorial Lecture). Proc. Royal Anthropological Inst.

 

of Great Britain and Ireland, pp. 15-25.
Cavalli-Sforza, L. L. 1974. The Role of Plasticity in Biological and
| Cultural Evolution. New York Acad. of Sci. 231:43-59.

Kidd, K.K. and Cavalli-Sforza, L.L. 1974. The Role of Genetic Drift in
The Differentiation of Icelandic and Norwegian Cattle. Evolution
(In press).

Sgaramella-Zonta, L. and Cavalli-Sforza, L.L. 1973. A metho? of the
detection of a demic cline. Proceedings, Workshop on Population
Structure, Hawaii University Press, pp. 128-135.

Yasuda, N., Cavalli-Sforza, L.L., Skolnick, M. and Moroni, A. 1974.

The evolution of surnames. An analysis of their distribution and —
extinction. Theoretical Population Biology 5:123-142.
Cavalli-Sforza, L. L. and Piazza, A. 1974. Analysis of Human Evolution.
- . I. Evolutionary Rates, Independence sand Treeness.
Am. J. Hum. Genet. (submitted for publication).

Piazza, A., Sgaramella-Zonta, L., Gluckman, P., Cavalli-Sforza, L. 1974.
Analysis of Human Evolution. II. Phylogenetic analysis of a
sample of 35 human populations tested for HLA and other markers.
Am. J. Hum. Genet. (in preparation).

Cavalli-Sforza, L. L. 1974. Human Population Genetics. Scientific
American (in press).

Ammerman, A., Cavalli-Sforza, L. and Wagener, D. 1974. Towards the
Estimation of Population Growth in Old World Prehistory.

Proc. Soc. for American Archaeology, Smithsonian Inst., May, 1974.
FISCAL DATA FOR CURRENT BUDGET PERIOD

October 1, 1973 to September 30, 1974

 

 

BUDGET CATEGORIES AWARDED ACTUAL ESTIMATED TOTAL BALANCE
EXPEND. EXPEND.
05/31/74 REMAINDER
BUDG. PER.
Salaries/St. Benef. $17,201 $3,413 $10,779 $14,192 $3,009
Computer Time 4,083 $6,936 6,936 -2,853
Others 500 656 656 - 156
$21,784 $11,005 $10,779 $21,784 0
Indirect Costs $10,238 5,282 4,956 $10,238 0
$32,022 $16,287 $15,735 $32,022