Unified Universal Seesaw Models

A set of Grand Unified Theories based upon the gauge groups SU(5)_\L \times SU(5)_\R, SO(10)_\L \times SO(10)_\R and SU(4)_\C \times SU(4)_\L \times SU(4)_\R is explored. Several novel features distinguish these theories from the well-known $SU(5)$, $SO(10)$ and SU(4)_\C \times SU(2)_\L \times SU(2)_\R models which they generalize. Firstly, Standard Model quarks and leptons are accompanied by and mix with heavy SU(2)_\L \times SU(2)_\R singlet partners. The resulting fermion mass matrices are seesaw in form. Discrete parity symmetries render the determinants of these mass matrices real and eliminate CP violating gauge terms. The unified seesaw models consequently provide a possible resolution to the strong CP problem. Secondly, \sinsq at the unification scale is numerically smaller than the experimentally measured $Z$ scale value. The weak angle must therefore increase as it evolves down in energy. Finally, proton decay is suppressed by small seesaw mixing factors in all these theories.Comment: 22 pages with 2 figures not included but available upon request, CALT-68-185

Fermion masses and mixing angles from gauge symmetries

The structure of the quark and lepton masses and mixing angles provides one of the few windows we have on the underlying physics generating the \sm. In an attempt to identify the underlying symmetry group we look for the simplest gauge extension of the SUSY standard model capable of generating the observed structure. We show that the texture structure and hierarchical form found in the (symmetric) quark and lepton mass matrices follows if one extends the gauge group of the standard model to include an horizontal $U(1)$ gauge factor, constrained by the need for anomaly cancellation. This $U(1)$ symmetry is spontaneously broken slightly below the unification/string scale leaving as its only remnant the observed structure of masses and mixings. Anomaly cancellation is possible only in the context of superstring theories via the Green Schwarz mechanism with $sin^2(\theta_W)=3/8$.Comment: 19 pages, preprint numbers OUTP-9403 and FTUAM-94/7, LaTe

Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

<p>Abstract</p> <p>Background</p> <p>Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly <it>MLH1 </it>and <it>MSH2</it>, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.</p> <p>Methods</p> <p>We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.</p> <p>Results</p> <p>The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among <it>MLH1 </it>mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in <it>MSH2 </it>carriers (about 54%). The relative risk associated with <it>MLH1 </it>was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for <it>MSH2 </it>decreased with age (from 13.1 at age 30 to 5.4 at age 70).</p> <p>Conclusion</p> <p>This study provides a unique population-based study of CRC risks among <it>MSH2</it>/<it>MLH1 </it>mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.</p

Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models

<p>Abstract</p> <p>Background</p> <p>Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias.</p> <p>Methods</p> <p>A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females.</p> <p>Results</p> <p>Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders.</p> <p>Conclusion</p> <p>The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.</p