Mendel

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The Mendel software program performs likelihood-based statistical analysis to solve a variety of genetic problems. Implementations are included for all common, and several novel, statistical genetic tests. Data sets can consist of qualitative or quantitative traits, pedigree or population samples, limited loci or dense SNPs. Where appropriate, the analysis will use either the Elston-Stewart or Lander-Green-Kruglyak algorithms, whichever is more efficient for each individual pedigree.

Mendel includes options to:

  1. order and map a set of markers along a chromosome;
  2. use parametric linkage methods to localize a gene on a fixed marker map;
  3. use non-parametric linkage (NPL) methods to localize a gene on a fixed marker map;
  4. estimate haplotypes;
  5. identify potential genotyping errors;
  6. test for allelic association by the TDT or the gamete-competition model;
  7. determine kinship coefficients conditional on marker data;
  8. perform genetic risk calculations;
  9. test for paternity or other pedigree relationships;
  10. estimate allele frequencies using either pedigrees or a random sample;1
  11. estimate trait genotype penetrances;
  12. estimate ethnic composition using pedigree data;
  13. identify deviations from Hardy-Weinberg and linkage equilibrium;
  14. simulate genetic data by gene dropping;
  15. localize QTLs, including X-linked QTLs, using variance component analysis;
  16. perform association analysis on quantitative traits;
  17. test for association given linkage; and
  18. trim pedigrees to a core group and all necessary connecting relatives.
  19. dense SNP genotype imputation, including haplotypes.
  20. dense SNP association testing, including rare variants.
  21. maternal-fetal genotype incompatibility test.
  22. inbred strain QTL analysis.
  23. simulate trait values incorporating major loci and various models.

Contact and Citation Information

Contact Information:

Kenneth Lange

mendel@genetics.ucla.edu

Citation:

Lange K, Cantor R, Horvath S, Perola M, Sabatti C, Sinsheimer J, Sobel E (2001) Mendel version 4.0: A complete package for the exact genetic analysis of discrete traits in pedigree and population data sets. Amer J Hum Genetics 69(supplement):504.

New Features

New Features in Mendel Version 12

In this update we have added one new option, Trait Simulation, and improved several of the existing options. The new option uses either existing genotype data or the output of the genotype simulation option to determine trait values. The traits can be either univariate (simulated by generalized linear models) or multivariate (simulated by variance component models). Mean effects due to the genotypes at a major locus can be included in the model. The list of supported distributional families for the mean effects model is substantial (see Tables 14.1 and 14.2 in the Documentation).

Genotype simulation now allows various output styles. In addition, one has considerable control over the degree of missing data for both trait and genotype simulation. This flexibility is accomplished with the introduction of four new keywords:: GENE_DROP_OUTPUT, KEEP_FOUNDER_GENOTYPES, MISSING_AT_RANDOM, and MISSING_DATA_PATTERN.

Since a grand mean (intercept) is required for each trait in all of Mendel's regression analyses, it is now added automatically. Thus it is no longer necessary to add commands such as PREDICTOR = GRAND :: trait to your model. It does no harm if you continue to include such commands explicitly.

An important change has been made to the meaning of the weight that can be assigned to each SNP in the SNP definition file. These predictor weights are used when building the best regression model that includes the user-specified number of predictors. A weight can now be any positive real number. Also, the greater the weight, the more likely the predictor will be included in the model. If the keyword UNIFORM_WEIGHTS has the value True, which is the default, then all predictors with unassigned weights receive weight 1.0. Otherwise, SNPs with unassigned weights receive weight 1/sqrt{4q(1-q)}, where q is the minor allele frequency at the SNP. (If you previously included weights in your SNP definition files, we suggest you now use the inverse of the old weights.)

Other minor changes include the maximum number of loci that can be combined into a superlocus has been increased from four to five. The keyword SEED can now be set to the special value TIME, which sets the seed based on the current time. The value set is reported in the standard output file.

New Features in Mendel Version 11

This revision incorporates two new options and several improvements to existing options. The new options are Maternal-Fetal Genotype Incompatibility Testing and Inbred Strains Analysis. The first of the new options facilitates modeling of interactions between maternal and child genotypes. The classic example is Rh maternal-fetal incompatibility. The second of the new options represents a new approach to QTL mapping with inbred strains of mice and other animals. The option implements a mixed effects model that correctly captures polygenic background, handles multivariate traits, and copes with pedigrees of arbitrary complexity. The QTL effect is modeled at the mean level as a vector of regression coefficients on the strain origin pair (maternal-paternal) imputed for each animal at the current QTL location along the genome.

To better deal with rare SNPs, the SNP Association option has been significantly improved. In an expanded version of the SNP Definition file, for each SNP one can now assign a weight and membership in a group of SNPs, e.g., a gene or molecular pathway. Default weights can be based on allele frequencies. The lasso regression can now use group penalties, which make it easier to understand association at the gene level rather than the SNP level. The new keyword LASSO_PROPORTION specifies the relative importance the model puts on individual predictors versus predictor groups. One may also specify individual predictors, or groups of predictors, to always retain in the LASSO model by using the keywords RETAINED_PREDICTOR and RETAINED_GROUP. Finally, in interaction testing, it is now possible to test for all pairwise interactions in a large base set of predictors.

Among the modification of existing features, we have introduced a better facility for imposing linear constraints on parameters. See the discussion of the new keyword PARAMETER_EQUATION in the documentation.

The SNP Imputation option now performs both pedigree based and linkage disequilibrium based genotype and haplotype inference. The combination of these two approaches leads to more accurate imputation results. Better imputation in turn leads to better handling of missing data and presumably more sensitive SNP association tests.

New Features in Mendel version 10

In this revision several analysis options have been expanded to add useful new features. For example, both SNP imputation and association testing now work on X-linked SNPs. The only caveat is that for SNP imputation, either all or none of the SNPs in each data set should be X-linked. SNP association testing of case-control data is now much faster, often more than five times faster. This is accomplished at the expense of calculating regression coefficients for only at least marginally significant SNPs. The cutoff p-value significance level can be set via the new keyword ESTIMATION_THRESHOLD, which has default value 0.001. Also, SNP association analysis can be performed under any of three dominance models: codominant (the default), first allele dominant, or first allele recessive. Alternatively, each SNP can automatically be analyzed under all three models, and the most significant result reported. The model is chosen by setting the new keyword SNP_DOMINANCE_MODEL to one of: Codominant, Dominant, Recessive, or Maximum.

All high-density SNP based analyses now permit filtering the individuals and SNPs included in the analysis. Filtering is based on genotyping success rates. The minimum genotyping rates allowed for included individuals and SNPs are set via the new keywords MIN_SUCCESS_RATE_PER_INDIVIDUAL and MIN_SUCCESS_RATE_PER_SNP. Both keywords have default values 0.98.

The NPL option has been expanded to allow the analysis of quantitative variables. The new Q-NPL statistic is discussed in the documentation. For the Location Score analysis option, the trait locus should now be named using the keyword AFFECTED_LOCUS_OR_FACTOR, and no longer need be included in the Map file. (Old files with the trait locus indicated by the first locus in the Map file will continue to work.) The positions analyzed outside the left and rightmost markers are now set using the new keywords FLANKING_DISTANCE and FLANKING_POINTS. In a change from past versions, the values of the keywords FLANKING_DISTANCE and GRID_INCREMENT now always have the same units as the distances in the Map file, which recall is set using the keyword MAP_DISTANCE_UNITS. Finally, for the location score option, a new example data set is added which illustrates the use of the simple PENETRANCE keyword to define a penetrance function.

Any comments, suggestions, and questions regarding Mendel are welcome at mendel@genetics.ucla.edu.

Mendel 2012 Software License Agreement

Please read and specify that you agree or disagree at the bottom of this document.

Name of software being licensed: MENDEL

THIS IS A LEGAL AGREEMENT BETWEEN YOU (EITHER AS AN INDIVIDUAL OR ENTITY) AND KENNETH L. LANGE. BY INSTALLING THIS SOFTWARE, YOU ARE CONSENTING TO BE BOUND BY AND ARE BECOMING A PARTY TO THIS AGREEMENT. IF YOU DO NOT AGREE TO ALL OF THE TERMS OF THIS AGREEMENT, DO NOT INSTALL MENDEL.

THIS LICENSE COVERS ONLY THE YEAR 2012 AND THE FIRST THREE MONTHS OF THE FOLLOWING YEAR. AT THE EXPIRATION OF THIS LICENSE, YOU MUST DESTROY ANY COPIES OF MENDEL OBTAINED UNDER THIS LICENSE. IF YOU WISH TO CONTINUE USING MENDEL, THEN YOU MUST DOWNLOAD A NEW COPY AND AGREE TO A NEW LICENSE.

TERMS OF THE LICENSE:

FEES: You may download Mendel as often as necessary, free of charge.

RESTRICTIONS: You may NOT

(a) copy, redistribute, post, or otherwise enable or permit other individuals to access or use MENDEL except under the terms listed herein;

(b) permit concurrent use of the Software except under the terms listed herein;

(c) modify, translate, reverse engineer, decompile, disassemble, or create derivative works based on MENDEL;

(d) rent, lease, grant a security interest in, or otherwise transfer rights to Mendel; or

(e) remove or put any proprietary notices or labels on MENDEL.

TITLE: Title, ownership rights, and intellectual property rights in MENDEL shall remain with Kenneth Lange. MENDEL is protected by copyright and other intellectual property laws and by international treaties.

DISCLAIMER OF WARRANTY: MENDEL IS PROVIDED AS IS WITHOUT WARRANTY OF ANY KIND. KENNETH LANGE MAKES NO REPRESENTATIONS AND EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, AND NONINFRINGEMENT. THE ENTIRE RISK ARISING OUT OF THE USE OR PERFORMANCE OF MENDEL AND ITS DOCUMENTATION REMAINS WITH LICENSEE. IN NO EVENT SHALL KENNETH LANGE BE LIABLE FOR ANY CONSEQUENTIAL, INCIDENTAL, DIRECT, INDIRECT, SPECIAL, PUNITIVE, OR OTHER DAMAGES WHATSOEVER (INCLUDING, WITHOUT LIMITATION, DAMAGES FOR LOSS OF BUSINESS PROFITS, BUSINESS INTERRUPTION, LOSS OF BUSINESS INFORMATION OR OTHER PECUNIARY LOSS) ARISING OUT OF THIS AGREEMENT OR THE USE OF OR INABILITY TO USE MENDEL.

INSTALLATION: LICENSEE warrants and represents that a competent System Administrator will install MENDEL, and that the System Administrator will carefully review all documentation, manual pages, and release notes included with MENDEL prior to installation.

USE: LICENSEE agrees to provide KENNETH LANGE with a report of any errors encountered in LICENSEE'S use of MENDEL.

RISK: The entire risk as to the use and performance of MENDEL is assumed by LICENSEE. LICENSEE shall defend, indemnify and hold harmless KENNETH LANGE AND HIS EMPLOYER, THE UNIVERSITY OF CALIFORNIA, for and against any and all claims, demands, damages, losses, and expenses of any kind (including but not limited to attorneys' fees), relating to or arising from any use or disposition by LICENSEE or its transferees of MENDEL.

MAINTENANCE: Neither KENNETH LANGE nor the UNIVERSITY OF CALIFORNIA is obligated to provide maintenance, technical support, interpretation of results, or updates for MENDEL.

TERMINATION: This license will terminate automatically if you fail to comply with the limitations described herein. On termination, you must destroy all copies of the Software and Documentation.

ACKNOWLEDGEMENT: LICENSEE agrees to reference MENDEL in every publication that employs it. See the top of every standard output file generated by MENDEL for the preferred citation to use.