Mark Billadeau Posted February 3, 2012 Report Share Posted February 3, 2012 I finally got Mark Neff on the phone for a quick call. I asked for a short written update (what he had time to provide) on the Border Collie projects. Below is what he sent me. I'm hoping on meeting with in next week in DC. I was asked to write something briefly to let the community know the progress that has been made on the hearing loss study in Border Collies. In addition to the previous work that has been reported at herding trials, etc, we have now sequenced two Border Collie dogs entirely; this is the only breed for which we have sequenced multiple dogs. The data that we have generated puts forth nearly a hundred candidates for the causal mutation for hearing loss. This is a wealth of riches -- too many good leads. We are sorting through these candidate mutations. We have considered sequencing a third dog to accelerate the process even more. If the community wanted to consider supporting this initiative, we would be delighted to provide additional details on how we could make this happen. I would also like to note that we are in the process of transitioning our informatics, which is our computational platform for not only managing data, but also tracking DNA collection kits. This is a major change (and a major improvement is underway!), but it has indeed disrupted our ability to ship and track kits to breeders and owners interested in participating. I assure you that we do indeed have every intention of collecting and analyzing additional DNA samples. We hope to resume this activity (and send kits to those of you who have requested them) ASAP. We appreciate your patience. Mark Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 3, 2012 Author Report Share Posted February 3, 2012 I hope to check on this thread later this weekend, but for now I need to head home to help with a ewe having lambing issues. Mark Link to comment Share on other sites More sharing options...
abcollie Posted February 3, 2012 Report Share Posted February 3, 2012 I hope to check on this thread later this weekend, but for now I need to head home to help with a ewe having lambing issues. Mark THANK YOU Mark ... very much appreciated!!! Good luck with the ewe. Link to comment Share on other sites More sharing options...
Journey Posted February 3, 2012 Report Share Posted February 3, 2012 Umm, ok, can someone translate? Do they have *anything* or do they need more funding because there are too many candidates? Link to comment Share on other sites More sharing options...
juliepoudrier Posted February 3, 2012 Report Share Posted February 3, 2012 It sounds to me like they want/need more funding to be able to sequence a third dog because that would help them to narrow the candidate genes to something more workable.... ETA: I suppose it could also mean that they need additional candidate dogs for sequencing, though I think those would be readily available. I wonder what's going on with the epi study? J. Link to comment Share on other sites More sharing options...
abcollie Posted February 3, 2012 Report Share Posted February 3, 2012 It sounds to me like they want/need more funding to be able to sequence a third dog because that would help them to narrow the candidate genes to something more workable.... ETA: I suppose it could also mean that they need additional candidate dogs for sequencing, though I think those would be readily available. I wonder what's going on with the epi study? J. I was told they had not asked nor received money from ABCA? Is that not correct? I'm just glad someone is getting this moving ... seems like it stalled out awhile ago???! Link to comment Share on other sites More sharing options...
Maralynn Posted February 3, 2012 Report Share Posted February 3, 2012 I requested kits, but that was about 6 months ago now and I never got anything. Is that the disruption that he is talking about? Are they still planning on sending those out at some time if a person requested them? Link to comment Share on other sites More sharing options...
Pam Wolf Posted February 3, 2012 Report Share Posted February 3, 2012 I would like to see the work on this issue continue. I know people whose dogs are affected by early onset deafness and I hear a lot of 'excuses' why dogs 'don't hear too good'. This is a real problem within the breed and the sooner the information is out there the sooner people can knowledgably breed to lines without worrying about putting in 3-5 years of hard work only to discover their dog is going deaf. Link to comment Share on other sites More sharing options...
juliepoudrier Posted February 3, 2012 Report Share Posted February 3, 2012 Mara, It sounded as if they would be sending out the backlog of requested kits once they got the database upgraded. At least that's how I interpreted Dr. Neff's comments above. Candy, I don't know if ABCA gave them funding or not. It may be that ABCA's only involvement has been encouraging people to submit samples.... Oh, and I doubt the work actually stalled; I just think they quit communicating when the results didn't come as quickly as they'd hoped. J. Link to comment Share on other sites More sharing options...
Liz P Posted February 4, 2012 Report Share Posted February 4, 2012 Dr. Neff was kind enough to show me his data at the genetics conference. He had a single spike (one gene) on the map for all adult onset hearing loss Border Collies. At that time he said the disease was caused by a single recessive gene. Did he explain what he meant by "100 mutations"? Link to comment Share on other sites More sharing options...
Pearse Posted February 4, 2012 Report Share Posted February 4, 2012 Mara, It sounded as if they would be sending out the backlog of requested kits once they got the database upgraded. At least that's how I interpreted Dr. Neff's comments above. Candy, I don't know if ABCA gave them funding or not. It may be that ABCA's only involvement has been encouraging people to submit samples.... Oh, and I doubt the work actually stalled; I just think they quit communicating when the results didn't come as quickly as they'd hoped. J. The ABCA did not give them any money. They did not request any funding from ABCA. Pearse Link to comment Share on other sites More sharing options...
nancyp Posted February 4, 2012 Report Share Posted February 4, 2012 At the Klamath Finals, Dr Neff was asked if ABCA money was needed , He said that they had gotten a HUGE grant and that no money was needed from ABCA. Nancy Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 4, 2012 Author Report Share Posted February 4, 2012 Dr Neff stopped all processing of requests for kits because of how inefficient their system was for collecting and storing information about the dogs. They are working on a new system. When that is ready they will start processing requests for kits again. From what I can tell, what started as a few good candidates for EOD markers were specific to the first smaller set of dogs tested. When the the number of dogs was increased these markers did not pan out; however, many more popped out as candidates and they are working their way through them. To help guide them they sequenced 2 Border Collies a normal and one with EOD. The number of dogs in the world that have been fully sequenced is <10. Having 2 Border Collies in this very small group should say something about how serious they are about working on our genetic diseases. Dr Neff said that he knew from when he left UCDavis that communication between his group and the breed associations they are working with was critical and the most difficult problem he would need to address. He knows this problem has not been solved and he has some ideas that may help which he is exploring. Link to comment Share on other sites More sharing options...
Journey Posted February 4, 2012 Report Share Posted February 4, 2012 Thanks Mark. Link to comment Share on other sites More sharing options...
juliepoudrier Posted February 4, 2012 Report Share Posted February 4, 2012 Dr Neff said that he knew from when he left UCDavis that communication between his group and the breed associations they are working with was critical and the most difficult problem he would need to address. He knows this problem has not been solved and he has some ideas that may help which he is exploring. Interesting. When I talked to Alison last year we discussed communications/PR and I *volunteered* to do some writing for them, since science communication is the field in which I worked for decades. J. Link to comment Share on other sites More sharing options...
Liz P Posted February 4, 2012 Report Share Posted February 4, 2012 Do they have a new estimate for the release date of a test? Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 5, 2012 Author Report Share Posted February 5, 2012 Liz, in research it is difficult to put a time line on successfully completing a project. It would be like putting a time line on when a pup will be competently competing in open. You can guess based upon past successes but each project/pup is different with its own issues. Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 5, 2012 Author Report Share Posted February 5, 2012 Good luck with the ewe. Water bag came out Friday and the ewe was not dilated or having contractions. Went in and pulled the lambs; both were fully developed and died shortly after being pulled. Ewe seems to be recovering but will be leaving since she has had lambing issues 2 years in a row. Link to comment Share on other sites More sharing options...
abcollie Posted February 5, 2012 Report Share Posted February 5, 2012 Water bag came out Friday and the ewe was not dilated or having contractions. Went in and pulled the lambs; both were fully developed and died shortly after being pulled. Ewe seems to be recovering but will be leaving since she has had lambing issues 2 years in a row. Shame ... hate to loose lambs but "good job" saving the ewe. With the price of sheep (similar to "gold bars" around here)... should help a little with the loss (not that anything really does :@( Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 14, 2012 Author Report Share Posted February 14, 2012 I met with Dr Neff for 1.5hrs last week in DC. I thought I'd share some notes I made from this meeting. Kits At the time of our meeting Dr Neff's lab did not have an efficient means to collect and store information about dogs, samples, test results, etc. They have been storing the information in several locations and formats; owner/breeder info in one location, sample information in another, test results in another, etc. This inefficiency had finally reached a critical point where it had to be resolved. Dr. Neff had his people stop processing requests for kits until this was resolved. He thought the resolution was going to be available any day; therefore, he did not communicate the interruption to the public. Any day dragged on, and on, and on. He now has someone working on a laboratory information management system (large database with easy to use interface for inputting and searching the data). At the time of the meeting the system was close to being ready to go live. They will resume processing requests for kits once this system is up and running. EOD (Early Onset Deafness) Research Overview SNP testing of Borders Collies has found a locus (3 million base pairs) in which there is a recessive gene responsible for EOD. The data is very conclusive. This is what he was telling us at the VA Finals. Their next step was to sequence 2 working Border Collies with EOD and compare to dogs of other breeds which were fully sequenced. Mark assures me that the other breeds are the appropriate controls for finding genetic markers for a functional defect like EOD. In a recessive disease the pairs of chromosomes in these two EOD Border Collies will be identical at the location of the genetic marker (genetic variant) for EOD; while the other dogs will not have this variant. The variant could be an insertion, a deletion, or a change in the sequence. When they compare the 3 million base pair region of the locus in the EOD dogs to the other sequenced dogs they found 100s of variants; most of these variants are in non-coding portions of the genome. Of the remaining variants in the coding regions, there are none that are only in the EOD dogs; all of these variants are present to a small degree in the other dogs. This was the unexpected result which delayed the development of a test. There are several reasons why the EOD genetic marker was not obvious: the other breeds have unidentified EOD, the EOD gene occurs in a portion of the genome which they currently consider non-coding, the current state of testing technology is not allowing them to locate the genetic marker (the size of the marker, number of base pairs, is not currently detectable). Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 14, 2012 Author Report Share Posted February 14, 2012 In order for me to understand more of the details that were discussed in my meeting with Dr Neff I've been doing some reading on various genetic research terms and methods. I found this one on SNP helpful. This abstract for the CEA work was also helpful. Combined genotypes from affected individuals from four breeds of a single breed group significantly narrowed the candidate gene region to a 103-kb interval spanning only four genes. Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind. This work both establishes that the primary cea mutation arose as a single disease allele in a common ancestor of herding breeds as well as highlights the value of comparative population analysis for refining regions of linkage. Breed relationships facilitate fine-mapping studies: A 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds The CEA gene is a deletion of 7800 base pairs. Compare this to the 3 million base pair locus in which the EOD gene is located. The current EOD research has not been able to "narrow the candidate gene region" down as was stated in the beginning of the CEA abstract above. This helps me understand where the EOD research is in relation to how the CEA research progressed. Based upon the note from Acland on the Optigen CEA page the CEA research progressed like this: 1989 (before) "go-normals", have been clinically recognized 2000 Collie eye anomaly in the rough collie in Sweden: genetic transmission and influence on offspring vitality 2003 mapping paper (found genetic marker) 2005 Optigen releases DNA test for CEA Link to comment Share on other sites More sharing options...
Liz P Posted February 14, 2012 Report Share Posted February 14, 2012 Is he comparing affected Border Collies with affected Cavaliers? They seem to have the same type of hearing loss. That might help him narrow down the location. Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 14, 2012 Author Report Share Posted February 14, 2012 He was unaware of any other breeds with well documented EOD. Do you know of any studies with BAER results demonstrating EOD in Cavaliers? I have passed this link to Mark Neff. http://www.cavalierh...rg/deafness.htm Nevermind, this is from the link. 4April 2011: Researchers seek DNA swabs to study hearing loss in cavaliers. The Canine Genetics Group at the Van Andel Research Institute and the Translational Genomics Research Institute is studying DNA patterns that contribute to hearing loss in the CKCS. Thus far, the group has identified such DNA patterns for four other breeds.If you have a cavalier suspected of hearing loss, a saliva sample is all the group needs for the study. If you have an older cavalier with good hearing, the study needs DNA from those dogs, too, for "control" purposes. To obtain a free DNA kit, contact the Program for Canine Health and Performance at dogdna@tgen.org Include your mailing address and tell them the number of kits you need for both affected cavaliers and healthy cavaliers. Blood samples from affected CKCSs, drawn by veterinarians, also are needed. Contact Elissa Boguslawski at elissa.boguslawski@vai.org for blood sample submission instructions. Liz, I guess the answer to your question is YES. Link to comment Share on other sites More sharing options...
Mark Billadeau Posted February 14, 2012 Author Report Share Posted February 14, 2012 Wow, that was fast. Mark emailed and indicated it is not related to EOD based upon their testing results. Link to comment Share on other sites More sharing options...
Journey Posted February 14, 2012 Report Share Posted February 14, 2012 Thanks Mark. So, am I to understand that a marker could be more than 20 years out? Based on the CEA timeline and the tremendous base pair difference in EOD. Link to comment Share on other sites More sharing options...
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