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Background: The extent of linkage disequilibrium (LD) within a population determines the number of markers that will be required for successful association mapping and marker-assisted selection. Most studies on LD in cattle reported to date are based on microsatellite markers or small numbers of single nucleotide polymorphisms (SNPs) covering one or only a few chromosomes. This is the first comprehensive study on the extent of LD in cattle by analyzing data on 1,546 Holstein-Friesian bulls genotyped for 15,036 SNP markers covering all regions of all autosomes. Furthermore, most studies in cattle have used relatively small sample sizes and, consequently, may have had biased estimates of measures commonly used to describe LD. We examine minimum sample sizes required to estimate LD without bias and loss in accuracy. Finally, relatively little information is available on comparative LD structures including other mammalian species such as human and mouse, and we compare LD structure in cattle with public-domain data from both human and mouse., Results: We computed three LD estimates, D', Dvol and r2, for 1,566,890 syntenic SNP pairs and a sample of 365,400 non-syntenic pairs. Mean D' is 0.189 among syntenic SNPs, and 0.105 among non-syntenic SNPs; mean r2 is 0.024 among syntenic SNPs and 0.0032 among non-syntenic SNPs. All three measures of LD for syntenic pairs decline with distance; the decline is much steeper for r2 than for D' and Dvol. The value of D' and Dvol are quite similar. Significant LD in cattle extends to 40 kb (when estimated as r2) and 8.2 Mb (when estimated as D'). The mean values for LD at large physical distances are close to those for non-syntenic SNPs. Minor allelic frequency threshold affects the distribution and extent of LD. For unbiased and accurate estimates of LD across marker intervals spanning < 1 kb to > 50 Mb, minimum sample sizes of 400 (for D') and 75 (for r2) are required. The bias due to small samples sizes increases with inter-marker interval. LD in cattle is much less extensive than in a mouse population created from crossing inbred lines, and more extensive than in humans., Conclusion: For association mapping in Holstein-Friesian cattle, for a given design, at least one SNP is required for each 40 kb, giving a total requirement of at least 75,000 SNPs for a low power whole-genome scan (median r2 > 0.19) and up to 300,000 markers at 10 kb intervals for a high power genome scan (median r2 > 0.62). For estimation of LD by D' and Dvol with sufficient precision, a sample size of at least 400 is required, whereas for r2 a minimum sample of 75 is adequate.

Two novel methods for genome wide selection (GWS) were examined for predicting the genetic merit of animals using SNP information alone. A panel of 1,546 dairy bulls with reliable EBVs was genotyped for 15,380 SNPs that spanned the whole bovine genome. Two complexity reduction methods were used, partial least squares (PLS) and regression using a genetic algorithm (GAR), to find optimal solutions of EBVs against SNP information. Extensive internal cross-validation was used tofind the best predictive models followed by external validation (without direct use of the pedigree or SNP location). Both PLS and GAR provided both accurate fit to the training data set for somatic cell count (SCC) (max r = 0.83) and fertility (max r = 0.88) and showed an accuracy of prediction of r = 0.47 for SCC, and r = 0.72 for fertility. This is the first empirical demonstration that genome wide selection can account for a very high proportion of additive genetic variation in fitness traits whilst exploiting only a small percentage of available SNP information, without use of pedigree or QTL mapping. PLS was computationally more efficient than GAR.

Bulldog dwarfism in Dexter cattle is one of the earliest single-locus disorders described in animals. Affected fetuses display extreme disproportionate dwarfism, reflecting abnormal cartilage development (chondrodysplasia). Typically, they die around the seventh month of gestation, precipitating a natural abortion. Heterozygotes show a milder form of dwarfism, most noticeably having shorter legs. Homozygosity mapping in candidate regions in a small Dexter pedigree suggested aggrecan (ACAN) as the most likely candidate gene. Mutation screening revealed a 4-bp insertion in exon 11 (2266&#95;2267insGGCA) (called BD1 for diagnostic testing) and a second, rarer transition in exon 1 (-198C>T) (called BD2) that cosegregate with the disorder. In chondrocytes from cattle heterozygous for the insertion, mutant mRNA is subject to nonsense-mediated decay, showing only 8% of normal expression. Genotyping in Dexter families throughout the world shows a one-to-one correspondence between genotype and phenotype at this locus. The heterozygous and homozygous-affected Dexter cattle could prove invaluable as a model for human disorders caused by mutations in ACAN.

Analysis of data on 1000 Holstein-Friesian bulls genotyped for 15,036 single-nucleotide polymorphisms (SNPs) has enabled genomewide identification of haplotype blocks and tag SNPs. A final subset of 9195 SNPs in Hardy-Weinberg equilibrium and mapped on autosomes on the bovine sequence assembly (release Btau 3.1) was used in this study. The average intermarker spacing was 251.8 kb. The average minor allele frequency (MAF) was 0.29 (0.05-0.5). Following recent precedents in human HapMap studies, a haplotype block was defined where 95% of combinations of SNPs within a region are in very high linkage disequilibrium. A total of 727 haplotype blocks consisting of > or =3 SNPs were identified. The average block length was 69.7 +/- 7.7 kb, which is approximately 5-10 times larger than in humans. These blocks comprised a total of 2964 SNPs and covered 50,638 kb of the sequence map, which constitutes 2.18% of the length of all autosomes. A set of tag SNPs, which will be useful for further fine-mapping studies, has been identified. Overall, the results suggest that as many as 75,000-100,000 tag SNPs would be needed to track all important haplotype blocks in the bovine genome. This would require approximately 250,000 SNPs in the discovery phase.

We have adapted the Location Database (LDB) map-integration strategy of Morton et al. [Ann Hum Genet 56:223-232] (1992) as above to create an integrated map for each of several species for which fully annotated genome sequences are not yet available (sheep, cattle, pig, wallaby), using all types of partial maps for that species, including cytogenetic, linkage, somatic-cell hybrid, and radiation hybrid maps. An integrated map provides not only predictions of the kilobase location of every locus, but also predicts locations (in cM) and cytogenetic band locations for every locus. In this way a comprehensive linkage map and a comprehensive cytogenetic map are created, including all loci, irrespective of whether they have ever been linkage mapped or physically mapped, respectively. High-resolution physical maps from annotated sequenced species have also been placed alongside the integrated maps. This has created a powerful tool for comparative genomics. The LDB map-integration strategy has been extended to make use of zoo-FISH comparative information. It has also been extended to enable the creation of a "virtual" map for each species not yet sequenced by using mapping data from fully sequenced species. All of the partial maps, together with the integrated map, for each species have been placed in a database called Comparative Location Database (CompLDB), which is available for querying, browsing, or download in tabular form at http://medvet.angis.org.au/ldb/.

We describe a pedigree-analysis approach to estimating descriptive epidemiological parameters for autosomal-recessive disorders when the ancestral source of the disorder is known. We show that the expected frequency of carriers in a cohort equals the gene contribution of the ancestral source to that cohort, which is equivalent to the direct (additive) genetic relationship of that ancestor to the cohort. Also, the expected incidence of affected foetuses ranges from (1/2)F* to F*, where F* is the mean partial inbreeding coefficient (due to the ancestor) of the cohort. We applied this approach to complex vertebral malformation (CVM) in Holstein-Friesians in Australia, for which the ancestral source is a USA-born bull, Carlin-M Ivanhoe Bell. The estimated frequency of carriers was 2.47% for the 1992-born and 4.44% for the 1997-born cohort of Holstein-Friesian cows in Australia. The estimated incidence of affected foetuses/calves was considerably less than one per thousand, ranging from 0.0024 to 0.0048% for the 1992-born cohort, and from 0.0288 to 0.0576% for the 1997-born cohort. These incidences correspond to expected numbers of affected female foetuses/calves ranging from 2 to 4 for the 1992-born cohort and from 28 to 56 for the 1997-born cohort. This approach is easy to implement using software that is readily available.

Background: Cattle are important agriculturally and relevant as a model organism. Previously described genetic and radiation hybrid (RH) maps of the bovine genome have been used to identify genomic regions and genes affecting specific traits. Application of these maps to identify influential genetic polymorphisms will be enhanced by integration with each other and with bacterial artificial chromosome (BAC) libraries. The BAC libraries and clone maps are essential for the hybrid clone-by-clone/whole-genome shotgun sequencing approach taken by the bovine genome sequencing project., Results: A bovine BAC map was constructed with HindIII restriction digest fragments of 290,797 BAC clones from animals of three different breeds. Comparative mapping of 422,522 BAC end sequences assisted with BAC map ordering and assembly. Genotypes and pedigree from two genetic maps and marker scores from three whole-genome RH panels were consolidated on a 17,254-marker composite map. Sequence similarity allowed integrating the BAC and composite maps with the bovine draft assembly (Btau3.1), establishing a comprehensive resource describing the bovine genome. Agreement between the marker and BAC maps and the draft assembly is high, although discrepancies exist. The composite and BAC maps are more similar than either is to the draft assembly., Conclusion: Further refinement of the maps and greater integration into the genome assembly process may contribute to a high quality assembly. The maps provide resources to associate phenotypic variation with underlying genomic variation, and are crucial resources for understanding the biology underpinning this important ruminant species so closely associated with humans.

We analysed linkage disequilibrium (LD) in Australian Holstein-Friesian cattle by genotyping a sample of 45 bulls for 15 closely-spaced microsatellites on two regions of BTA6 reported to carry important QTL for dairy traits. The order and distance of markers were based on the USDA-MARC linkage map. Frequencies of haplotypes were estimated using the E-M approach and a more computationally-intensive Bayesian approach as implemented in PHASE. LD was then estimated using the Hedrick multiallelic extension of Lewontin normalised coefficient D'. Estimates of D' from the two approaches were in close agreement (r = 0.91). The mean estimates of D' for marker pairs with an inter-marker distance of less than 5 cM (n = 13) are 0.57 and 0.51, and for distances more than 20 cM (n = 44) are 0.29 and 0.17, estimated from the E-M and Bayesian approaches, respectively. The Malecot model was fitted for the exponential decline of LD with map distance between markers. The swept radii (the distance at which LD has declined to 1/e ( approximately 37%) of its initial value) are 11.6 and 13.7 cM for the above two methods, respectively. The Malecot model was also fitted using map distance in Mb from the bovine integrated map (bovine location database, bLDB) in addition to cM from the MARC map. Overall, the results indicate a high level of LD on chromosome 6 in Australian dairy cattle.

We constructed a metric linkage disequilibrium (LD) map of bovine chromosome 6 (BTA6) on the basis of data from 220 SNPs genotyped on 433 Australian dairy bulls. This metric LD map has distances in LD units (LDUs) that are analogous to centimorgans in linkage maps. The LD map of BTA6 has a total length of 8.9 LDUs. Within the LD map, regions of high LD (represented as blocks) and regions of low LD (steps) are observed, when plotted against the integrated map in kilobases. At the most stringent block definition, namely a set of loci with zero LDU increase over the span of these markers, BTA6 comprises 40 blocks, accounting for 41% of the chromosome. At a slightly lower stringency of block definition (a set of loci covering a maximum of 0.2 LDUs on the LD map), up to 81% of BTA6 is spanned by 46 blocks and with 13 steps that are likely to reflect recombination hot spots. The mean swept radius (the distance over which LD is likely to be useful for mapping) is 13.3 Mb, confirming extensive LD in Holstein-Friesian dairy cattle, which makes such populations ideal for whole-genome association studies.

Mortality records of 1302 juvenile crocodiles were available for analysis. Crocodiles that were slaughtered during this study were treated as censored (n = 2151). Additionally, records from animals that had neither died nor been slaughtered, i.e. were still alive in the production system (n = 1582), were censored at the last date of data collection. There were a total of 3733 censored records. The data were all full-sib records from 29 parental pairs from Janamba Croc Farm (Northern Territory, Australia), collected over nine consecutive years. Data were analysed using an extension of Cox's proportional hazards model to include frailty (random) terms to account for genetic effects. Heritability of log survival time for juvenile crocodile survival was 0.15 (SE 0.04). The probability of a juvenile crocodile surviving to day 400 was estimated to be only 51%. These results are the first to quantify juvenile survival in a captive breeding situation. Also, this is the first heritability estimate of crocodile survival and is a fundamental element in the development of a genetic improvement programme.

A total of 3156 scale row records, comprising 1739 full-sibling records from 30 families from Janamba Croc Farm (NT, Australia) and 1417 parent-offspring records from 19 families from Wildlife Management International, Pty Ltd (NT, Australia), collected at each facility using a different method, were analysed using ASReml. The full-sibling heritability estimate for the Janamba data was 0.37 (SE 0.03). The animal model estimate of heritability for the Wildlife Management International (WMI) data, also based predominantly on full-sibling data, was 0.42 (SE 0.04). The counts from three counting methods were evaluated by regression analysis on 100 individuals and were found to be highly correlated. Using the regression relationship, the WMI data were transformed and pooled with the Janamba data to give an animal model heritability estimate of 0.42 (SE 0.04). A multitrait analysis revealed negligible correlations (both phenotypical and genetical) between hatchling size traits and the number of scale rows. There is ample genetic variation to incorporate this trait into a genetic improvement programme for farmed saltwater crocodiles.

Online Mendelian Inheritance in Animals (OMIA) is a comprehensive, annotated catalogue of inherited disorders and other familial traits in animals other than humans and mice. Structured as a comparative biology resource, OMIA is a comprehensive resource of phenotypic information on heritable animal traits and genes in a strongly comparative context, relating traits to genes where possible. OMIA is modelled on and is complementary to Online Mendelian Inheritance in Man (OMIM). OMIA has been moved to a MySQL database at the Australian National Genomic Information Service (ANGIS) and can be accessed at http://omia.angis.org.au/. It has also been integrated into the Entrez search interface at the National Center for Biotechnology Information (NCBI; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=omia). Curation of OMIA data by researchers working on particular species and disorders has also been enabled.

This online database uses a search facility that allows users to select from the 180 recognized dog breeds in Australia and find out which ones are prone to the more than 500 inherited disorders on record. It was developed in consultation with a number of supporting organizations, including the local breeders' governing body and animal-welfare groups, as well as owners. It is hoped that, although primarily for veterinary education, the Web site will increase awareness among breeders and may encourage them to adopt breeding programs that decrease the occurrence of the most prevalent disorders.

Crocodile morphometric (head, snout-vent and total length) measurements were recorded at three stages during the production chain: hatching, inventory [average age (+/-SE) is 265.1 +/- 0.4 days] and slaughter (average age is 1037.8 +/- 0.4 days). Crocodile skins are used for the manufacture of exclusive leather products, with the most common-sized skin sold having 35-45 cm in belly width. One of the breeding objectives for inclusion into a multitrait genetic improvement programme for saltwater crocodiles is the time taken for a juvenile to reach this size or age at slaughter. A multivariate restricted maximum likelihood analysis provided (co)variance components for estimating the first published genetic parameter estimates for these traits. Heritability (+/-SE) estimates for the traits hatchling snout-vent length, inventory head length and age at slaughter were 0.60 (0.15), 0.59 (0.12) and 0.40 (0.10) respectively. There were strong negative genetic (-0.81 +/- 0.08) and phenotypic (-0.82 +/- 0.02) correlations between age at slaughter and inventory head length.

Repeatability and phenotypic correlations were estimated for saltwater crocodile reproductive traits. No pedigree information was available to estimate heritability or genetic correlations, because the majority of breeder animals on farms were wild-caught. Moreover, as the age of the female breeders could not be accounted for, egg-size measurements were used as proxies. The reproductive traits investigated were clutch size (total number of eggs laid), number of viable eggs, number of eggs that produced a live, healthy hatchling, hatchability, average snout-vent length of the hatchlings and time of nesting. A second data set was also created comprising binary data of whether or not the female nested. Repeatability estimates ranged from 0.24 to 0.68 for the measurable traits, with phenotypic correlations ranging from -0.15 to 0.86. Repeatability for whether a female nested or not was 0.58 on the underlying scale. Correlations could not be estimated between the measurement and binary traits because of confounding. These estimates are the first published for crocodilian reproduction traits.

Single-locus disorders in domesticated animals were among the first Mendelian traits to be documented after the rediscovery of Mendelism, and to be included in early linkage maps. The use of linkage maps and (increasingly) comparative genomics has been central to the identification of the causative gene for single-locus disorders of considerable practical importance. The 'score-card' in domestic animals is now more than 100 disorders for which the molecular lesion has been identified and hence for which a DNA test is available. Because of the limited lifespan of any such test, a cost-effective and hence popular means of protecting the intellectual property inherent in a DNA test is not to publish the discovery. While understandable, this practice creates a disconcerting precedent. For multifactorial disorders that are scored on an all-or-none basis or into many classes, the effectiveness of control schemes could be greatly enhanced by selection on estimated breeding values for liability. Genetic variation for resistance to pathogens and parasites is ubiquitous. Selection for resistance can therefore be successful. Because of the technical and welfare challenges inherent in the requirement to expose animals to pathogens or parasites in order to be able to select for resistance, there is a very active search for DNA markers for resistance. The first practical fruits of this research were seen in 2002, with the launch of a national scrapie control programme in the UK.

A highly fecund inbred mouse line has been established from the Quackenbush Swiss (QS) outbred strain by full-sib inbreeding combined with selection for high number of pups born alive (NBA) and low interlitter interval (ILI). After more than 50 generations of inbreeding and selection, this line, named QSi5, has an NBA of 13.4 and an ILI of 29 days, averaged over the first four parities, and a total productivity of 50.7 NBA. With its exceptional reproductive performance, this line will be very useful in the creation of resources (including advanced intercross lines) for analysis of quantitative trait loci for a wide range of traits, and for the cost-effective creation of congenic lines.

Online Mendelian Inheritance in Animals (OMIA) provides up-to-date information on inherited disorders and other familial traits in non-laboratory animals. It is freely available online at http://www.angis.org.au/omia. With a strong emphasis on comparative biology, OMIA is modelled on, and reciprocally hyperlinked with, Online Mendelian Inheritance in Man (OMIM). It provides a comprehensive catalog of animal models of human inherited disorders, and also provides comprehensive access to information on potential human homologues of inherited disorders and traits in animals. Because its whole structure is based on comparative biology, it provides phenotypic information in a format that is complementary to all the relevant mapping and sequence databases now existing or being created across the animal kingdom.

In 1997, neuronal ceroid lipofuscinosis (NCL) was identified for the first time in Merino sheep in Australia. A homozygosity mapping approach localized the disease gene in Merino sheep to the same region on chromosome 7 in which NCL was recently mapped in South Hampshire sheep. This region shows conserved synteny with the region on human chromosome 15 in which the human late infantile NCL variant CLN6 was mapped. NCL in Merino and South Hampshire sheep are therefore potential animal models for the human late infantile variant CLN6.

Current information on inherited disorders in domestic animals is available on the internet: Online Mendelian inheritance in animals (OMIA) and Mendelian inheritance in sheep (MIS) are the two major sources of information. OMIA was created (and is maintained) by workers at the University of Sydney. MIS has been compiled by the Committee on Genetic Nomenclature of Sheep and Goats (COGNOSAG), an international group of geneticists. In the future, similar catalogues for other species (starting with goats and cattle) will be made available by COGNOSAG. Electronic access to this information is freely accessible on the world-wide web at http:/(/)www.angis.su.oz.au/Databases/BIRX/om ia (for OMIA), http:/(/)probe.nalusda.gov:8300/animal/omia.h tml (for OMIA in the United States of America) and at http:/(/)www.angis.org.au/Databases/BIRX/mis (for MIS).

We investigated the pattern of inheritance of maternal meiotic errors responsible for a high frequency of triploid progeny in a selected line of chickens. For the genetic analysis, F1 and backcross populations were produced from crosses between normal diploid individuals of the triploidy line and a control line. Triploid embryos were produced by 35% and 67% of reciprocal F1 females and by 24% and 67% of reciprocal backcross females. These results exclude autosomal recessive and sex-linked recessive or sex-linked dominant inheritance. A single autosomal dominant gene is also not likely to be responsible. However, the results are consistent with the determination of triploidy by a single autosomal gene with no dominance, and an even better fit is obtained by two loci, an autosomal gene with no dominance and a sex-linked gene. The results cannot exclude a multifactorial mode of inheritance, but the rapid response to selection for triploidy and consistent expression of the meiotic errors in different genotypes suggest that meiotic mutations at one or two loci are the most plausible genetic basis for the trait.

Summary: Eight traits representing clinical indicators of resistance to footrot were examined in 1562 Merino sheep, representing the progeny from 162 sires in four major bloodlines. Over a 4-year period, sheep were exposed to virulent isolates of Dicbelobacter nodosus under both an experimental challenge in which footrot was induced, and a separate natural challenge involving a different isolate of D. nodosus. Five footrot traits and three healing traits were each recorded on seven occasions following induced challenge, and on five occasions following natural challenge. All sheep were vaccinated with a primary and booster injection of an homologous rDNA pilus vaccine, 9 and 6 weeks after initiation of the induced and natural challenge respectively. The major fixed effects which influenced variation in resistance were (in order of importance) time of inspection after challenge, year and group in which sheep were challenged, and sex of the animal. Date of birth, birth-rearing type and age or dam were unimportant in the expression of footrot. Half-sib heritability estimates of resistance to footrot were low to moderate for single observations recorded pre-vaccination (0.07-0.22), and slightly lower for inspections made after vaccination (0.07-0.15). Repeatability estimates for footrot traits during a challenge ranged from 0.31 to 0.70 for inspections pre-vaccination, and 0.19 to 0.35 for inspections post-vaccination. Genetic correlations among footrot traits recorded at repeat inspections were high for observations pre-vaccination (range 0.87-1.00) and slightly lower for observations made after vaccination (0.52-1.00). Heritability estimates derived from repeat measurements approached 0.30 for most traits, except for traits describing healing, which had a heritability of almost zero. Heritability estimates of liability to footrot ranged between 0.09 and 0.41 depending on the time after challenge when the inspections were made. The genetic correlation between induced and natural footrot ranged from 0.14 to 0.95, depending on the period over which inspections were made, with an average of 0.67. In addition to within-flock genetic variation in resistance to footrot, significant differences were observed between different bloodlines within the experimental flock. It was concluded that there is substantial genetic variation in resistance to challenge with virulent isolates of D. nodosus. However, practical restrictions of exploiting available genetic variation may limit the widespread adoption of direct selection. ZUSAMMENFASSUNG: Krankheitsresistenz in Merinos III. Genetische Variabilität in Moderhinke Resistenz nach Infektion und folgender Impfung mit homologer rDNA pilus Vakzine unter induzierten und natürlichen Bedingungen Acht Merkmale, die als klinische Hinweise auf Moderhinkeresistenz betrachtet werden, wurden in 1562 Merino Schafen aus 162 Vatertieren von vier wichtigen Linien untersucht. Über eine 4-Jahresperiode wurden die Schafe virulenten Isolaten von Dichelobacter nodosus unter Versuchsbedingungen ausgesetzt und eine getrennte natürliche Infektion mit verschiedenen Isolaten von D. nodosus durchgeführt. Fünf Moderhinkemerkmale und drei Gesundungsmerkmale wurden nach Infektion bei sieben Gelegenheiten festgehalten und an fünf nach natürlicher Infektion. Alle Schafe wurden mit einer primären und einer booster Injektion homologer rDNA pilus Vakzine geimpft, 9 und 6 Wochen nach der induzierten und natiirlichen Infektion. Die wichtigsten fixen Effekte, welche die Variabilität der Resistenz beeinflussen, waren, nach Wichtigkeit gereint, Zeit der Prüfung nach Impfung, Jahr und Gruppe in welcher Schafe geimpft wurden und Geschlecht. Geburtsdatum, Aufzuchttyp und Mutterschaf-alter waren im Hinblick auf Moderhinke unwichtig. Halbgeschwister-Heritabilitätsschätzungen ihrer Resistenz waren niedrig bis mittel für Einzelbeobachtungen vor der Impfung (0,07-0,22) und geringfügig geringer für Beurteilung nach Impfung (0,07-0,15). Wiederholbarkeitsschätzungen für Moderhinkemerkmale bewegten sich von 0,31 bis 0,70 für Inspektionen vor und 0,19-0,35 für Inspektionen nach Impfung. Genetische Korrelationen zwischen Moderhinkemerkmalen bei verschiedenen Untersuchungen waren fur Beobachtungen vor der Impfung hoch (0,87-1) und geringfügig niedriger nachher (0,52-1). Heritabilitätsschätzungen von wiederholten Messungen erreichten 0,30 für die meisten Merkmale außer für jene, welche Heilung beschreiben, die nahezu keine Heritabilität zeigen. Heritabilitätsschätzungen für Moderhinkeempfindlichkeit variierten zwischen 0,09 und 0,41 in Abhängigkeit von der Untersuchungszeit nach den Impfungen. Die genetische Korrelation zwischen induzierter und natürlicher Moderhinke schwankte von 0,14 bis 0,95 in Abhängikeit von der Dauer der Beobachtungsperiode, durschnittlich 0,67. Zusätzlich zur genetischen Variabilität innerhalb der Herde wurden signifikante Unterschiede zwischen verschiedenen Linien innerhalb der Versuchsherde gefunden. Darauf wird es geschlossen, daß substantielle genetische Variabilität für Resistenz gegenüber virulenten Isolaten von D. nodosus existiert. Allerdings können praktische Hindernisse die Ausnutzung der vorhandenen genetischen Variabilität durch direkte Selektion einschränken., (1994 Blackwell Verlag GmbH.)

Summary: RFLP analysis was used to investigate the effect of genetic variation in the Major Histocompatibility Complex (MHC) class II region on resistance of sheep to the intestinal parasite Trichostrongylus colubriformis, using faecal egg count (fec) as the measure of resistance. RFLP analysis of DNA from 335 sheep with the restriction enzymes TaqI, PvuII and HindIII, and DRB, DQA and DQB human class II MHC cDNA clones, revealed 238 bands, of which 233 were polymorphic. Sixteen bands were associated with a significant effect on fec, when analysed using a mixed model, best linear unbiased prediction statistical methods. However, when p values were corrected for the number of bands tested the associations were no longer significant. While no individual band had a significant effect on fec, Fisher's X(2) test of the distribution of p-values showed that RFLP bands, when considered together, do account for a significant proportion of variation in fec. One hundred and thirteen offspring from 11 halb-sib families were classified according to which MHC haplotype they had inherited from their sire. While there was overall no convincing statistical evidence of an effect of MHC haplotype on resistance, results in one family showed evidence for a repeatable MHC effect. ZUSAMMENFASSUNG: Die MHC-Klasse II Region und Resistenz gegenüber Darmparasiten beim Schaf RFLP Analyse betrifft die Auswirkung genetischer Unterschiede im Haupthistokompatibilitäts-Komplex (MHC) Klasse II Region auf Resistenz von Schafen gegen den Darmparasiten Trichostrongylus colubriformis, wobei die fäkale Eizahl (fec) als Maß der Resistenz verwendet worden ist. Die RFLP-Analyse der DNA von 335 Schafen mit Restriktionsenzymen TaqI, PvuII und HndIII und DRB, DQA und DQB menschlicher Klasse II MHC cDNA Klone ergab 238 Bande, wovon 233 polymorph waren. 16 Bande waren mit einer signifikanten Wirkung auf fec verbunden, wobei zur Analyse das gemischte Modell der BLUP verwendet worden ist. Allerdings, nach Korrektur der p-Werte für die Zahl der geprüften Bande zeigt sich die Assoziation nicht länger als signifikant. Während kein individuelles Band eine signifikante Wirkung auf FEC zeigte, ergab Fisher's test hinsichtlich Verteilung der p-Werte Signifikanz bei Gesamtbetrachtung. 113 Nachkommen von 11 Halbgeschwister-Familien wurden nach dem MHC Haplotyp des Vatertieres klassifiziert. Es ergab sich kein insgesamt überzeugender statistischer Hinweis auf Wirkung der MHC Haplotypen, doch in einer Familie Hinweis auf wiederholbare MHC Effekte., (1993 Blackwell Verlag GmbH.)

Summary: Clinical and serological responses were monitored in sheep following experimental challenge with footrot and subsequent vaccination with an homologous rDNA pilus vaccine. Twenty-two clinical indicators of footrot were identified to describe differences between feet, between sheep, between flocks, and over time. All eleven between-sheep indicators were significantly correlated with each other (0.47 to 0.96). However, analyses of liability on a underlying scale showed that those indicators with several categories, such as the number of feet affected or underrun, were most useful: the data strongly indicated that increasing grades of severity reflect a single underlying variable. The proportion of sheep affected and/or underrun (i.c.e. prevalence) was the most suitable indicator of flock differences. Repeatability of footrot scores over time was relatively low (0.36 to 0.56 prior to vaccination; 0.02 to 0.30 after vaccination), highlighting the need for repeat observations to describe differences in footrot over time. A need was shown to incorporate spontaneous or induced healing following vaccination in scoring systems for footrot. Serological assays detected an increase in antibody titres during infection, but antibody titres were not sufficiently correlated with clinical indicators (0.34 to 0.61) to justify their use as indicators of footrot. K-agglutination titres were moderately to highly correlated with Pili ELISA assays (0.69 to 0.86), but the two types of assay are not interchangeable. On balance, K-agglutination is the most appropriate measurement of antibody response for all types of footrot studies. This set of initial analyses has shown large phenotypic variation in all important footrot indicators. Subsequent studies will investigate the extent to which there is genetic variation in these indicators, with the aim of determining the feasibility of incorporating resistance to footrot into breeding programmes. The traits defined and described in this paper from the basis of a large scale investigation into genetic and phenotypic aspects of resistance to footrot. ZUSAMMENFASSUNG: Krankheitsresistenz bei Merinos. I. Moderhinkeresistenz nach experimenteller Infektion und Impfung mit homologer rDNA-pilus vaccine Klinische und serologische Reaktionen wurden nach experimenteller Infektion von Schafen mit Moderhinke und folgender Impfung mit homologer rDNA-pilus vaccine verfolgt. 22 klinische Symptome wurden identifiziert um Unterschiede zwischen Füßen, zwischen Schafen, Herden und Zeitspannen zu beschreiben. Alle elf "zwischen Schaf" Symptome waren signifikant miteinander korreliert (0,47 bis 0.96). Die Analysen der Liabilität auf zugrundeliegender Skala zeigt allerdings, daß Symptome mit mehreren Kategorien, wie etwa Zahl der befallenen Füße, am nützlichsten waren: Die Daten weisen darauf hin, daß steigende Erkrankungsgrade eine zugrundeliegende Variable wiedergeben. Der Anteil der befallenen Schafe und/oder lose Klauen gaben am besten Herdendifferenzen wieder. Wiederholbarkeit von Moderhinke über einen Zeitraum war relativ niedrig (0,36 bis 0,56 vor der Vaccination; 0,02 bis 0,30 nachher), wodurch Notwendigkeit wiederholter Beobachtungen der Moderhinke deutlich wird. Notwendigkeit zur Berücksichtigung spontaner oder medikamentös verursachter Heilung nach Impfung in dem Beurteilungssysteme für Moderhinke ist gegeben. Serologisch konnte ein Anstieg von Antikörperspiegel während der Infektion festgestellt werden, doch waren diese nicht hinreichend eng mit klinischen Symptomen verbunden (0,34 bis 0,61), um sie als Moderhinkemerkmale betrachten zu können. K-Agglutinationsspiegel waren mäßig bis stark mit Pili ELISA-Werten korreliert (0,69 bis 0,86), doch waren die beiden nicht auswechselbar. Insgesamt erscheint K-Agglutination das beste Maß der Antikörperreaktion in allen Arten von Moderhinkeuntersuchungen zu sein. Diese anfänglichen Analysen zeigten große phänotypische Variabilität in allen wichtigen Moderhinkesymptomen. Folgende Studien werden das Ausmaß genetischer Ursachen dieser Symptome untersuchen mit dem Ziel, Moderhinkeresistenz in Zuchtprogrammen zu berücksichtigen. Die in dieser Arbeit definierten und beschriebenen Merkmale bilden die Basis einer größeren Untersuchung über genetische und phänotypische Aspekte der Moderhinkeresistenz., (1993 Blackwell Verlag GmbH.)

Summary: Restriction fragment length polymorphism (RFLP) within the Major Histocompatibility Complex (MHC) Class II region was examined in 83 sheep. Two restriction enzymes (TaqI and PvuII) and two human cDNA probes (DQα-folke and DRβ-malta) were used to probe Southern blots from all sheep. In addition, a second human DRβ probe (signe) and the restriction enzyme, EcoRI, were used for 15 sheep to match previously published polymorphism in sheep using the same probe/enzyme combination. All sheep were part of an experiment in which footrot was experimentally induced and then controlled through vaccination with an homologous rDNA pilus vaccine. The four main probe/enzyme combinations detected extensive polymorphism; in total 74 bands were detected of which only 2 were present in all sheep. A similar level of polymorphism was also seen with the EcoRI/DRβ-signe probe/enzyme combination, which was greater than previously published for sheep, cattle or goats. After accounting for cross-hybridising bands, the sheep DRβ region appeared to be more polymorphic than the DQα region. Similarly the TaqI restriction enzyme revealed more polymorphism than the PvuI enzyme (40 and 34 bands respectively). For all 74 bands, 7 main clusters were identified both within and across probe/enzyme combinations. After removing bands/clusters which were of extreme frequency (< 0.10 and > 0.90), a total of 53 bands/clusters were analysed for their potential association with footrot and antibody responses. One band was significantly associated with susceptibility to footrot over the 27-week period during which footrot was measured. In addition, two single bands and one cluster were significantly (P > 0.001) associated with residual footrot infection after vaccination. Nine bands/clusters were associated with antibody titre during infection, and one cluster with antibody titre after vaccination. These results suggest a possible involvement for genetic polymorphism within the ovine Class II region in variation in response to footrot. ZUSAMMENFASSUNG: Krankheitsresistenz bei Merinos, II. RFLP's in Klasse II MHC und ihre Verbindung mit der Moderhinkeresistenz Restriktionsfragmentlängenpolymorphismus (RFLP) innerhalb des Haupthistokompatibilitätskomplexes (MHC) Klasse II Region wurde bei 83 Schafen untersucht. Zwei Restriktionsenzyme (TaqI und PvuII) und zwei humane cDNA-Sonden (DQα-folke und DRβ-malta) wurden für Southern blots bei allen Schafen verwendet. Zusätzlich wurde eine zweite humane DRβ-Sonde (signe) und das Restriktionsenzym EcoRI bei 15 Schafen zum Vergleich mit früher publizierten Polymorphismus mit den selben Enzym/Sondenkombinationen durchgeführt. Alle Schafe waren Teil eines Versuches, in welchem Moderhinke experimentell induziert und dann durch Vaccination mit homologer rDNA-pilus vaccine bekämpft worden war. Die 4 Enzym/Sondenkombinationen entdeckten extensiven Polymorphismus. Insgesamt 74 Banden wurden entdeckt, wovon nur zwei in allen Schafen vorhanden waren. Ein ähnliches Ausmaß von Polymorphismus wurde auch mit der EcoRI/DRβ-signe Enzym/Sondenkombination entdeckt, das größer war als bisher für Schafe, Rinder oder Ziegen publiziert. Nach Berücksichtigung der Kreuz-Hybridisierungsbande scheint die Schaf-DRβ-Region stärker polymorph als die DQα-Region zu sein. Ähnlicherweise zeigte das TaqI Restriktionsenzym mehr Polymorphismus als das PvuII Enzym (40 bzw. 34 Bande). Bei allen 74 Banden wurden sieben Hauptkluster identifiziert, sowohl innerhalb als auch über Enzym/Sondenkombinationen. Nach Entfernung von Banden/Kluster mit extremen Häufigkeiten (< 0,10 bzw. > 0.9) wurden insgesamt 53 Bande/Kluster hinsichtlich ihrer potentiellen Verbindung mit Moderhinke und Antikörperreaktion analysiert. Ein Band war signifikant mit Moderhinkeempfindlichkeit während der 27-Wochenperiode assoziiert. Zusätzlich waren zwei einzelne Bande und ein Kluster signifikant (p > 0,001) assoziiert mit Moderhinkeinfektion nach der Impfung. 9 Band/Kluster waren mit Antikörperspiegel während der Infektion verbunden und ein Kluster mit Antikörperspiegel nach Impfung. Die Ergebnisse deuten auf Zusammenhang des genetischen Polymorphismus innerhalb der ovinen Klasse II-Region mit Variabilität im Moderhinkeverlauf., (1993 Blackwell Verlag GmbH.)

The P-M system of transposition in Drosophila melanogaster is a powerful mutator for many visible and lethal loci. Experiments using crosses between unrelated P and M stocks to assess the importance of transposition-mediated mutations affecting quantitative loci and response to selection have yielded unrepeatable or ambiguous results. In a different approach, we have used a P stock produced by microinjection of the ry506 M stock. Selection responses were compared between transposition lines that were initiated by crossing M strain females with males from the "co-isogenic" P strain, and ry506 M control lines. Unlike previous attempts to quantify the effects of P element transposition, there is no possibility of P transposition in the controls. During 10 generations of selection for the quantitative trait abdominal bristle number, none of the four control lines showed any response to selection, indicative of isogenicity for those loci affecting abdominal bristle number. In contrast, three of the four transposition lines showed substantial response, with regression of cumulative response on cumulative selection differential ranging from 15% to 25%. Transposition of P elements has produced new additive genetic variance at a rate which is more than 30 times greater than the rate expected from spontaneous mutation.

An A in equilibrium with G transition in exon III is known to differentiate alleles A and B of the cattle beta-lactoglobulin (BLG) gene. A BLG exon III fragment containing the transition site was amplified by the polymerase chain reaction. Temperature gradient gel electrophoresis (TGGE) was then used to detect this transition and hence to genotype cattle: the AT base-pair in allele A was readily distinguished from the GC base-pair of allele B. TGGE can be used to detect any single base-pair substitution, and thus is a powerful method of detecting genetic variability.

Natural infestations of the cattle tick Boophilus microplus, levels of the buffalo fly Haematobia irritants exigua and faecal nematode egg concentrations (Bunostomum phlebotomum, Cooperia spp., Haemonchus placei, Oesophagostomum radiatum and Trichostrongylus axei) were assessed in 221 Belmont Red calves during the post-weaning period, when the animals were between 9 and 18 months of age. In addition, the 98 males of this group were challenged with B. microplus larvae on two separate occasions. There were strong positive correlations among replicate assessments of the same parasite. Field tick counts and tick counts following deliberate challenge were strongly correlated, and both showed negative correlations with post-weaning weight gain. There was a weak positive correlation between buffalo fly counts and post-weaning weight gain. There was a negative correlation between total worm egg count and weight gain. Among worm species, only the effect of O. radiatum on weight gain was significant. Cattle with bovine major histocompatibility (BoLA) antigens W6.1 and W7 had significantly fewer ticks than cattle lacking these antigens. Cattle with BoLA antigens W7 and CA36 had lower concentrations of nematode eggs in their faeces than cattle lacking these BoLA antigens.

Lymphocytes from 1,564 cattle of 18 breeds and cross-bred groups in Australia were tested for major histocompatibility system class 1 antigens. Gene frequencies were calculated for the Angus, Belmont Red, Brahman, Hereford and Holstein-Friesian breeds. There were substantial differences among these breeds in antigen and gene frequency. There were striking differences among all 18 breeds in the presence or absence of certain antigens. Two antigens, CA13 and CA36, were strongly associated in Hereford cattle but occurred independently of each other in the other breeds.

We tested 53 cattle with ocular squamous cell carcinoma (cancer-eye) and 53 paired, matched controls for 25 class I antigens of the bovine major histocompatibility system. The most common antigen was W5 which was present in 40% of the animals with cancer-eye and 36% of the controls. There were no statistically significant differences in BoLA antigen frequency between cattle with and cattle without cancer-eye.

In Canberra, 31 antigens have been described on the surface of bovine lymphocytes. Seven antigens are subgroups of other antigens. Eleven antigens are similar to the eleven antigens which have been described in Melbourne. Fourteen antigens are similar to twelve international-workshop antigens and two European-workshop antigens.

Two consecutive calf crops consisting of 141 three-quarters Brahman/one-quarter Shorthorn cattle were assessed for resistance to the Australian cattle tick Boophilus microplus in May, July and October 1983. Although the level of expressed resistance to artificial infestation varied considerably between seasons, the animals maintained very similar rankings for resistance in all three seasons, and the repeatability of tick resistance ranged from 0.59 to 0.82. The cattle were typed for 30 bovine class I lymphocyte antigens. Antigens W6 and CA31 were associated with susceptibility to artificial tick infestation but none of the other lymphocyte antigens showed strong associations with resistance or susceptibility.

199 3/4 Brahman 1/4 Shorthorn cattle, whose resistance to the cattle tick Boophilus microplus had been determined by clinical trial, were tested for 19 bovine lymphocyte antigens. Of eleven antigens detected at a frequency greater than 5%, two were found to be associated with tick resistance and a third was associated with susceptibility to ticks. However, none of these antigens accounts for more than 2.1% of the variance, indicating that these associations are not strong.

The association between bovine major histocompatibility system (BoLA) type and persistent lymphocytosis in cattle with antibodies to bovine leukaemia virus was examined by comparing antigen frequencies in cattle with persistent lymphocytosis to controls matched for age, sex, breed and presence of antibodies to BLV. The cattle came from nine dairy herds in south-east Queensland, Australia; six herds were Australian Illawarra Shorthorn (AIS), two herds were Jersey and one herd was Friesian. Antigen W6 and Eu28R were more common in cattle with persistent lymphocytosis than in controls. Antigen W8 was less common in AIS cattle with persistent lymphocytosis. A study of 24 offspring from one sire, heterozygous for W10 and Eu28R, showed that offspring inheriting Eu28R from the sire were significantly more likely to have antibodies to BLV than offspring inheriting the opposing W10 haplotype.

Two fertile male tortoiseshell Burmese cats with atypical coat color distribution were found to have normal 38XY karyotypes. Synaptonemal complex analysis of one of these cats revealed normal meiotic pairing. Progeny data indicated that both cats were transmitting both alleles at the sex-linked orange locus, but with unequal frequencies. For one of these cats, analysis of pedigree and progeny data indicated that gene instability at the orange locus was the only possible explanation for its mosaicism. A third male tortoiseshell Burmese cat with typical tortoiseshell phenotype was found to be 39XXY and sterile.

The history of simple segregation analysis is reviewed with the aim of clarifying the present confusion in terminology. Although Weinberg's contribution to simple segregation analysis is considerable, it is noted that he was not responsible for one of the methods often attributed to him. For the benefit of biologists attempting to understand simple segregation analysis, the various names given by different authors to some of the methods of segregation analysis that are still in use are incorporated into a table. All the confusion in terminology can be avoided, however, by using an extension (due to Davie) of the singles method that combines a very simple and efficient estimate of segregation frequency with a very quick and simple estimate of its variance, and that is valid for all levels of ascertainment.

The effect of directional and heterotic selection on the standardized variance of gene frequency (f=σ q (2) /¯q(1-¯q)) has been examined. It has been found that heterotic selection always results in f values lower than those expected due to drift alone. Additive directional selection can result in low f values, but values larger than those expected due to drift will be observed under additive selection with low initial gene frequency, or when the populations have been separated for a very long period of time in which case f expected due to drift is quite high (around 0.7 or greater). The effect of selection on f is unlikely to be detected if the observed value of f is less than 0.1.

The nature and extent of negative and multiple HLA antigen disease associations are investigated theoretically under two models. The first model assumes that an HLA antigen is involved directly in predisposing individuals to disease. The second model assumes that the association of a particular HLA antigen(s) with a disease is the result of linkage disequilibrium between the allele determining the antigen and alleles at a nearby locus which confers susceptibility to disease. We determined whether observed decreases in antigen frequencies among a patient group are simply the inevitable result of the fact that if one or more alleles at a locus is increased in frequency, then others must be decreased. Under the antigen predisposing model exact predictions concerning allele and antigen class frequencies at the predisposing locus, and the non-predisposing loci, are given. The predictions are examined using HLA-DR data for multiple sclerosis.

The effect of t ' generations of reverse selection after t generations of forward selection can be described by expressing the change in the metric mean resulting from reverse selection (R) interms ofthe change in the metric mean due to the previous forward selection (Δx). An additive model of artificial selection in a population of effective size N with no natural selection has been considered.If reverse selection is continued for as many generations as the previous forward selection (t'=t), then the ratio R/Δx equals 1 - F where F is the inbreeding coefficient for a neutral locus at generation t and is estimated as [1-(1-1/2N)(t)]. The result of a single generation of reverse selection (t'=1) following t generations of forward selection can be described in terms of the ratio NR1/ηDx where R1 is the response to the first generation of reverse selection. The value of NR1/Δx is expected to be (1-F) /2F.For any period of reverse selection following any period of forward selection, the value of R/Δx never exceeds t '/t, and tends to decrease exponentially from this value as t increases.

Selection for post-weaning weight gain in mice from 21 to 42 days, on either a full or restricted feeding level during this period was carried out for seven generations. Control lines were maintained for each feeding level. The rate of selection response was higher on full feeding due to a higher heritability and a larger phenotypic variance. Realised heritabilities of 0.29±0.05 and 0.19±0.04 for selection on full and restricted feeding respectively, were in close agreement with base population estimates.Selection on full feeding led to positive correlated responses in 21 day weight, 42 day weight, food intake and efficiency between 21 and 42 days, and 42 day tail length, but with little change in reproductive performance.Correlated responses to selection on restricted feeding were reduced 21 day weight, but an increase in 42 day weight and increased efficiency from 21 to 42 days. However, overall reproductive performance fell.