So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

The primary purpose of this narrative review was to evaluate the current literature and to provide further insight into the role physical inactivity plays in the development of chronic disease and premature death. We confirm that there is irrefutable evidence of the effectiveness of regular physical activity in the primary and secondary prevention of several chronic diseases (e.g., cardiovascular disease, diabetes, cancer, hypertension, obesity, depression and osteoporosis) and premature death. We also reveal that the current Health Canada physical activity guidelines are sufficient to elicit health benefits, especially in previously sedentary people. There appears to be a linear relation between physical activity and health status, such that a further increase in physical activity and fitness will lead to additional improvements in health status.

/pdf/health-benefits-of-physical-activity-the-evidence-17tsp10zcy.pdf

Health benefits of physical activity: the evidence

A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

https://courses.washington.edu/gs466/readings/miki.pdf

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

CA : A Cancer Journal for Clinicians

Background Since falling is associated with serious morbidity among elderly people, we investigated whether the risk of falling could be reduced by modifying known risk factors. Methods We studied 301 men and women living in the community who were at least 70 years of age and who had at least one of the following risk factors for falling: postural hypotension; use of sedatives; use of at least four prescription medications; and impairment in arm or leg strength or range of motion, balance, ability to move safely from bed to chair or to the bathtub or toilet (transfer skills), or gait. These subjects were given either a combination of adjustment in their medications, behavioral instructions, and exercise programs aimed at modifying their risk factors (intervention group, 153 subjects) or usual health care plus social visits (control group, 148 subjects). Results During one year of follow-up, 35 percent of the intervention group fell, as compared with 47 percent of the control group (P = 0.04). The adjusted...

https://www.nejm.org/doi/pdf/10.1056/NEJM199409293311301

A multifactorial intervention to reduce the risk of falling among elderly people living in the community.

The familial risk of breast cancer is investigated in a large population-based, case-control study conducted by the Centers for Disease Control. The data set is based on 4,730 histologically confirmed breast cancer cases aged 20 to 54 years and on 4,688 controls who were frequency matched to cases on the basis of both geographic region and 5-year categories of age, and it includes family histories, obtained through interviews of cases and controls, of breast cancer in mothers and sisters. Segregation analysis and goodness-of-fit tests of genetic models provide evidence for the existence of a rare autosomal dominant allele (q = .0033) leading to increased susceptibility to breast cancer. The effect of genotype on the risk of breast cancer is shown to be a function of a woman's age. Although, compared with noncarriers, carriers of the allele appear to be at greater risk at all ages, the ratio of age-specific risks is greatest at young ages and declines steadily thereafter. The proportion of cases predicted to carry the allele is highest (36%) among cases aged 20-29 years. This proportion gradually decreases to 1% among cases aged 80 years or older. The cumulative lifetime risk of breast cancer for women who carry the susceptibility allele is predicted to be high, approximately 92%, while the cumulative lifetime risk for noncarriers is estimated to be approximately 10%.

Genetic analysis of breast cancer in the cancer and steroid hormone study.

Background. Improvements in screening techniques have made significant contributions to the early detection of breast cancer. Physicians thus face the task of providing appropriate screening schedules for their patients. One group for whom this is particularly important are those women with a family history of breast cancer.

Methods. In this report, data from the Cancer and Steroid Hormone Study, a population-based, case-control study conducted by the Centers for Disease Control, are used to provide age-specific risk estimates of breast cancer for women with a family history of breast cancer. The data set includes 4730 patients with histologically confirmed breast cancer age 20–54 years and 4688 control subjects who were frequency matched to patients by geographic region and 5-year age intervals. The data set also includes family histories of breast cancer in mothers and sisters of both patients and control subjects.

Results. Genetic models fit previously to these data by the authors have provided evidence for a rare autosomal dominant allele that results in increased susceptibility to breast cancer. In addition, these models predict that women who carry the allele are at greater risk of developing breast cancer at any age than are women who do not carry the allele. The increase in risk in carriers versus noncarriers does, however, decrease with increasing age. Based on the parameters of this model, age-specific risks for a woman with one or more relatives affected with breast cancer at various ages at onset are given.

Conclusions. These tables can be used for the purpose of counseling women at high risk of breast cancer development, that is, women with a family history of breast cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819940201%2973%3A3%3C643%3A%3AAID-CNCR2820730323%3E3.0.CO%3B2-5

Autosomal dominant inheritance of early‐onset breast cancer. Implications for risk prediction

BACKGROUND: Serious fall injury represents a little studied, yet common and potentially preventable, cause of morbidity and mortality among older persons. We determined the frequency of, and risk factors for, experiencing serious fall injury events among older persons in the community. SUBJECTS: A representative sample of 1103 community-living persons aged 72 years and older underwent comprehensive baseline and 1-year evaluations. MAIN OUTCOME MEASURES: During a median 31 months of follow-up, fall data were obtained using fall calendars. Injury data were obtained from telephone interviews and from surveillance of emergency room and hospital records. RESULTS: At least one fall was experienced by 546 (49%) participants. A total of 123 participants, representing 23% of fallers and 12% of the cohort, experienced 183 serious fall injury events. The factors independently associated with experiencing a serious injury during a fall included cognitive impairment (adjusted odds ratios 2.2; 95% confidence interval 1.5, 3.2); presence of at least two chronic conditions (2.0; 1.4, 2.9); balance and gait impairment (1.8; 1.3, 2.7); and low body mass index (1.8; 1.2, 2.5). In a separate analysis, including only subjects who fell, female gender (1.8; 1.1, 2.9) as well as most of the above factors were associated with experiencing a fall injury. CONCLUSIONS: Several readily identifiable factors appeared to distinguish the subgroup of older fallers at risk for suffering a serious fall injury. These factors should help guide who and what to target in prevention efforts. Language: en

Risk factors for serious injury during falls by older persons in the community.

Although most meningiomas are encapsulated and benign tumors with limited numbers of genetic aberrations, their intracranial location often leads to serious and potentially lethal consequences. They are the most frequently diagnosed primary brain tumor accounting for 33.8% of all primary brain and central nervous system tumors reported in the United States between 2002 and 2006. Inherited susceptibility to meningioma is suggested both by family history and candidate gene studies in DNA repair genes. People with certain mutations in the neurofibromatosis gene (NF2) have a very substantial increased risk for meningioma. High dose ionizing radiation exposure is an established risk factor for meningioma, and lower doses may also increase risk, but which types and doses are controversial or understudied. Because women are twice as likely as men to develop meningiomas and these tumors harbor hormone receptors, an etiologic role for hormones (both endogenous and exogenous) has been hypothesized. The extent to which immunologic factors influence meningioma etiology has been largely unexplored. Growing emphasis on brain tumor research coupled with the advent of new genetic and molecular epidemiologic tools in genetic and molecular epidemiology promise hope for advancing knowledge about the causes of intra-cranial meningioma. In this review, we highlight current knowledge about meningioma epidemiology and etiology and suggest future research directions.

/pdf/epidemiology-and-etiology-of-meningioma-ca2qtt8c1m.pdf

Elizabeth B. Claus

Papers

A multifactorial intervention to reduce the risk of falling among elderly people living in the community.

Genetic analysis of breast cancer in the cancer and steroid hormone study.

Autosomal dominant inheritance of early‐onset breast cancer. Implications for risk prediction

Risk factors for serious injury during falls by older persons in the community.

Epidemiology and etiology of meningioma.