Hum. Reprod. Advance Access published online on December 14, 2007
Human Reproduction, doi:10.1093/humrep/dem389
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Sperm aneuploidy frequencies analysed before and after chemotherapy in testicular cancer and Hodgkin's lymphoma patients
1 Department of Medical Genetics, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2 N 4N1 2 Department of Urology, McGill University Health Centre, Montreal, Canada 3 Department of Obstetrics and Gynaecology, McGill University, Montreal, QC, Canada H3G 1Y6 4 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6 5 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
6Correspondence address. Tel: +1-403-220-7520; Fax: +1-403-210-7931; E-mail: rhmartin{at}ucalgary.ca
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Abstract |
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BACKGROUND: Multicolour fluorescent in situ hybridization was utilized to detect sperm aneuploidy for chromosomes 13, 21, X and Y in testicular cancer and Hodgkin's lymphoma chemotherapy patients.
METHODS: Aneuploidy was assessed before, and 6, 12 and/or 18–24 months after, the initiation of chemotherapy, and compared with age matched controls. 635 396 sperm were scored blindly with 5000 sperm/patient/chromosome/ time point, where sperm was available. (First two phrases have been reversed).
RESULTS: Comparing testicular cancer and Hodgkin's lymphoma patients to each other and with controls, cancer-specific differences were identified. Hodgkin's lymphoma patients, particularly, exhibited significantly increased aneuploidy frequencies for all chromosomes throughout treatment. At 6 months, all cancer patients showed significantly increased frequencies of XY disomy and nullisomy for chromosomes 13 and 21. In general, aneuploidy frequencies declined to pretreatment levels 18 months after treatment initiation, but increased aneuploidy frequencies persisted in some chromosomes for up to 24 months.
CONCLUSIONS: Because of elevated aneuploidy frequencies prior to and up to 24 months from the start of chemotherapy, patients should receive genetic counselling about the potentially increased risk of an aneuploid conceptus from sperm cryopreserved prior to chemotherapy, and for conceptions up to 2 years after the initiation of treatment.
Key words: FISH/chemotherapy/aneuploidy/cancer/sperm chromosomes
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Introduction |
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Testicular cancer and Hodgkin's lymphoma are often diagnosed during a patient's reproductive years and are the most common malignancies among adolescent and young men (Birch et al., 2002
; Wu et al., 2003). Improved management of cancer including detection and treatment has led to improved survival rates, with 85–95% of testicular germ cell cancer patients and 66–89% of Hodgkin's lymphoma patients surviving at least 10 years (Hagemeister et al., 1982; Dahl, 1985; Longo et al., 1986). As a result, concerns have been raised about the consequences of anti-cancer treatment on fertility, particularly the potential genetic risk to future offspring.
To date, epidemiological studies have not shown an increased risk of congenital abnormalities, genetic disease or chromosome abnormalities in the offspring of male cancer survivors (Kenney et al., 1996; Martin et al., 1997a; Byrne et al., 1998; Blatt, 1999; Meistrich and Byrne, 2002; Green et al., 2003; Winther et al., 2004). These data are somewhat reassuring, but it should be noted that these studies have major shortcomings. The majority of reports were individual case studies or involved small sample sizes and thus would only be able to detect a 3- to 5-fold increase in abnormalities (Meistrich, 1993). A wide variety of mutagenic and non-mutagenic drugs and therapeutic regimes (differing doses, exposure and duration) were studied. In addition, the majority of cancer survivors were treated in childhood, and thus the evaluated pregnancies occurred long after treatment. As a result, these data do not reflect pregnancies that have resulted from germ cells exposed to chemotherapeutic agents during the sensitive time frame of gametogenesis (Frias et al., 2003; Wyrobek et al., 2005).
In mice, paternal exposure to irradiation or chemical mutagens followed by mating with unexposed females resulted in infertility, embryo lethality, transmissible chromosome translocations, congenital malformations, gene mutations and cancer in offspring (Wyrobek, 1993; Bishop et al., 1996; Witt and Bishop, 1996; Marchetti et al., 1997; Wyrobek et al., 2005). These animal studies have indicated that spermatocytes (meiotic cells), spermatids and spermatozoa (post-meiotic cells) are more sensitive to the induction of mutations than are pre-meiotic stem cells (Adler and El Tarras, 1990; Qiu et al., 1992). It is possible that the increased sensitivity of post-meiotic cells may be due to a reduced capacity for DNA repair in late spermatids and sperm compared with early spermatids and pre-meiotic cell types (Sotomayor and Sega, 2000). It is, however, difficult to extrapolate animal data to humans, given the species specificity to mutagens observed in different mammals (Hansmann and Probeck, 1979). Therefore, it is important to investigate the effect of chemotherapy on both pre-meiotic cells (post-chemotherapy) and meiotic and post-meiotic cells (during chemotherapy) (Carson et al., 1991; Martin et al., 1999). However, this is often impossible, as the chemotherapy treatment often causes azoospermia.
The effects of chemotherapeutic agents on sperm chromosomes can be studied by two methods: the hamster oocyte-human sperm fusion assay or multi-colour fluorescent in situ hybridization (FISH) (Martin et al., 1997b). Both of these techniques have advantages and disadvantages. The advantage of the sperm fusion assay is that information is generated on both numerical and structural abnormalities for all chromosomes. Disadvantages include the fact that it is costly, technically demanding, requires considerable time and is capable of analysing only a relatively small number of cells. The use of FISH is rapid, relatively inexpensive, technically simpler and capable of generating large data sets, but it provides aneuploidy information only on those chromosomes investigated and is of limited use in the detection of structural abnormalities.
This study used FISH to investigate aneuploidy frequencies for chromosomes 13, 21, X and Y in the sperm of men undergoing chemotherapy for either testicular cancer or Hodgkin's lymphoma. To determine whether chemotherapy caused increases in the frequencies of aneuploidy for the investigated chromosomes over the 24 month study period, samples were obtained prior to, and at one to three time points 6, 12 or 18–24 months after the initiation of chemotherapy treatment.
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There were 23 patients recruited to this study from the McGill University Health Centre, Montreal (testicular cancer n = 12 and Hodgkin's lymphoma n = 11), but samples could not be obtained throughout treatment for all patients due to patient drop-out and azoospermia. The study was therefore restricted to those patients from whom sperm samples were obtained for at least two time points. Using this criterion, sperm from five testicular cancer patients (average 26 years, range 21–28 years), five Hodgkin's lymphoma patients (average 24.8 years, range 19–36 years) and 10 age-matched healthy control donors (average 24.9 years, range 18–32 years) were analysed. The semen parameters in each male enrolled in this study were accessed at each time point, according to strict World Health Organization (WHO) guidelines (1999), and total sperm counts for patients can be found in Tables I and II. Testicular cancer patients were treated with 2–4 cycles of BEP chemotherapy (bleomycin, etoposide, cisplatin), and Hodgkin's lymphoma patients underwent 4–8 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastin, dacarbazine). No patients were treated with radiotherapy. All recruited individuals gave informed consent, and this research project was approved by institutional ethics committees.
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Sperm aneuploidy frequencies were analysed in the patient groups prior to and 6, 12 and/or 18–24 months after the initiation of treatment to study the effects on pre-meiotic cells. To enable comparisons to be drawn across the different time points between cancer types and with control donors, aneuploidy frequencies in control males were studied at the same time intervals.
To ensure blind scoring of samples, sperm specimens were coded before shipping on ice to Calgary for FISH analysis. Aneuploidy for chromosomes 13, 21, X and Y was analysed utilizing two-colour FISH for chromosomes 13 and 21 and three-colour FISH for the sex chromosomes (chromosome 1 was used as an internal autosomal control to distinguish diploidy from sex chromosome disomy). Approximately 5000 sperm/patient/chromosome probe set were scored, adhering to strict scoring criteria. These methods have been previously described in detail elsewhere (Spriggs et al., 1995). The proportion of aneuploid sperm (disomic, nullisomic and diploid) was analysed in two ways for the investigated chromosomes in both cancer types and controls. First, aneuploidy frequencies at all time points were analysed for each patient group to assess differences in the frequency of aneuploidy within the group across treatment. Second, at each time point, results for the three groups (testicular cancer, Hodgkin's lymphoma and controls) were compared with each other, enabling differences between the groups to be identified. Statistical analysis for both types of comparisons was carried out using the generalized estimating equation analysis (Zeger et al., 1988); results with P < 0.05 were considered significant.
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Results |
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A summary of the time points analysed in each of the controls and cancer patients can be found in Figure 1. A total of 635 396 sperm were analysed in this study, 320 121 for the sex chromosomes and 315 275 for chromosomes 13 and 21. Where sperm was available, a minimum of 5000 sperm was analysed per patient, per probe set. Tables I and II present aneuploidy results for sex chromosomes and chromosomes 13 and 21, respectively, at all time points in testicular cancer, Hodgkin's lymphoma and control donors.
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Sex chromosome results
When comparing aneuploidy frequencies for the sex chromosomes in testicular cancer and Hodgkin's lymphoma patient groups across treatment time points (Table I), statistically significant differences in aneuploidy were found for both groups. These included a significant increase in the frequency of XY disomy at 6 months compared with 12 months in both testicular cancer (0.21% versus 0.15%) and Hodgkin's lymphoma patients (0.28% versus 0.19%). Testicular cancer patients also had significantly increased XY disomy frequency 18–24 months after the initiation of treatment (0.23%) compared with 12 months (0.15%).
Several significant differences in sex chromosome aneuploidy were found when comparing the three groups (testicular cancer, Hodgkin's lymphoma and controls) at each time point (Table I). Prior to chemotherapy treatment, Hodgkin's lymphoma patients exhibited significantly increased XX disomy frequencies (0.05%) and sex chromosome nullisomy (1.06%) compared with testicular cancer patients (0.02%; 0.64%) and controls (0.02%; 0.58%). At 6 months, the frequency of XY disomy was higher in testicular cancer patients (0.21%) and in Hodgkin's lymphoma patients (0.28%) than in controls (0.13%).
Chromosomes 13 and 21 results
Aneuploidy frequencies for chromosomes 13 and 21 were also compared in both cancers across the different treatment intervals (Table II). There was a significant increase in disomy 21 in testicular cancer patients prior to treatment (0.19%) compared with frequencies at 12 and 18–24 months (0.09% and 0.08%, respectively). Testicular cancer patients also exhibited a significant increase in disomy 13 frequency at 18–24 months (0.22%) compared with pretreatment and 6 month frequencies (0.11% and 0.06%). The frequency of nullisomy 13 in Hodgkin's lymphoma patients was significantly increased at 6 months (0.37%) compared with pretreatment (0.24%) and 12 month frequencies (0.30%), and the 12 month frequency was significantly higher than that of later post-treatment time points (18–24 months; 0.27%). Testicular cancer patients also had a significantly increased frequency of chromosome 13 nullisomy at 6 months (0.20%) compared with 12 months (0.13%). The frequency of nullisomy 21 in Hodgkin's lymphoma patients was significantly higher prior to treatment (0.17%) than 12 months post-treatment (0.15%), and at 6 months (0.25%) compared with both pretreatment (0.17%) and 12 months (0.15%). In testicular cancer patients, nullisomy for chromosome 21 was significantly increased at 6 months (0.25%) compared with 12 months (0.10%).
When chromosome 13 and 21 aneuploidy frequencies (Table II) for each cancer type and in controls were compared with each other at each time point, several differences between groups were observed. At 6 months, the frequency of chromosome 13 disomy in Hodgkin's lymphoma patients (0.18%) was significantly higher than that of testicular cancer patients (0.06%). Nullisomy 13 frequencies in Hodgkin's lymphoma patients were elevated at 12 months (0.30%) and 18–24 months (0.27%) compared with those of the testicular cancer patients (0.13% and 0.08%). At 18–24 months, disomy frequencies for chromosome 21 in Hodgkin's lymphoma patients (0.26%) were significantly higher than those of both the control group (0.12%) and testicular cancer patients (0.08%). The frequency of chromosome 21 nullisomy in Hodgkin's lymphoma individuals was also significantly higher than that of controls prior to treatment (0.17% versus 0.08%) and 18–24 months post-treatment (0.11% versus 0.05%). In addition, Hodgkin's lymphoma patients had a higher proportion of diploid cells pretreatment (0.52%) compared with controls (0.21%) and testicular cancer patients (0.24%), and a higher frequency of diploid cells at 18–24 months compared with testicular cancer patients (0.57% versus 0.23%).
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Discussion |
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This study has demonstrated that both testicular cancer and Hodgkin's lymphoma patients had elevated frequencies of aneuploid sperm for chromosomes 13, 21 and the sex chromosomes coincident with chemotherapy. There were significantly increased aneuploidy frequencies 6 months after the initiation of treatment. For the most part, these frequencies declined to pretreatment levels
18 months after the initiation of treatment. Of particular interest are comparisons between the three groups: hodgkin's lymphoma patients had elevated proportions of aneuploidy for all chromosomes compared with both testicular cancer patients and controls throughout treatment. Testicular cancer patients had higher sex chromosome disomy frequencies at 6 months compared with controls, but not compared with Hodgkin's lymphoma patients. Furthermore, some pretreatment aneuploidy frequencies in testicular cancer and Hodgkin's lymphoma patients were elevated compared with control frequencies.
A handful of studies have investigated the effect of chemotherapy on sperm aneuploidy using both the hamster oocyte-human sperm fusion assay and FISH methods. Results from studies using the sperm fusion assay are divided: some indicate an increased frequency of abnormalities, whereas others show no increased risk; these studies have been reviewed in detail elsewhere (Martin et al., 1995, 1997a).
To date, a small number of studies have completed FISH analysis on the sperm of males who underwent chemotherapy for the treatment of several cancer types including testicular cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma. These studies can be divided into the following groups: investigations of post-treatment (6–60 months) aneuploidy frequencies only (Martin et al., 1995; De Mas et al., 2001; Thomas et al., 2004), those that investigated pretreatment levels only (Fait et al., 2001), those that have analysed pre- and post-treatment (82 days to 13 years) frequencies (Martin et al., 1997b, 1999; Robbins et al., 1997; Martin, 1998; Frias et al., 2003), and those which have also analysed sperm during chemotherapy treatment (35–65 days) (Robbins et al., 1997; Martin et al., 1999; Frias et al., 2003). These studies have been reviewed in detail elsewhere (Wyrobek et al., 2005; Martin, 2006), only those studies that have investigated aneuploidy frequencies prior to, during and post-treatment will be discussed further.
FISH aneuploidy analysis of chromosomes 1, 12, X and Y were analysed in four males undergoing BEP chemotherapy for testicular cancer pre-, during (35–65 days) and post-treatment (6–12 months) (Martin et al., 1999). Significant increases in the frequencies of XY disomy and diploidy were found during and post-treatment compared with controls. Aneuploidy frequencies for chromosomes 8, X and Y were investigated pre-, during (35–50 days) and post-chemotherapy (82–999 days) in eight patients undergoing NOVP chemotherapy for Hodgkin's lymphoma (Robbins et al., 1997). Significantly increased aneuploidy frequencies compared with controls were reported with up to a 5-fold increase in chromosome disomy and diploidy. These effects, however, were transient, with frequencies declining to pretreatment levels 100 days after treatment. Some individuals were also found to have significantly increased aneuploidy frequencies preceding treatment, when compared with controls. A similar study by the same group, investigating chromosomes 18, 21, X and Y in eight Hodgkin's lymphoma individuals treated by NOVP chemotherapy (Frias et al., 2003), found significant increases in all types of aneuploidy frequencies compared with controls, and noted chromosome specific variations (with a 2- to14-fold increase). In concordance with their earlier study (Robbins et al., 1997), these effects were transient and did not persist 1–2 years following treatment. The frequency of aneuploidy prior to treatment also appeared to be slightly higher than in controls.
It should be noted that in each of these studies, data were not available for each patient at all time points, so pre-, during- and post-chemotherapy data were not necessarily obtained from the same patients. Within the current study, some of the same difficulties in following individual patients at every investigated time point were also encountered, but pretreatment and at least one post-treatment samples were analysed for all patients. To the best of our knowledge, this is the largest study to date in which aneuploidy frequencies in the same patients are followed from before treatment through to the return of spermatogenesis in two types of cancer patients. Despite this, the number of patients studied is still relatively small, and larger scale studies involving more patients and chromosomes will be helpful in furthering our understanding of the effect of cancer and/or chemotherapy on spermatogenesis and meiosis.
The results from sperm karyotype and FISH studies are not conclusive, and are difficult to compare due to a number of factors: patients in different studies have different cancer types and treatments, in a number of studies there are small patient numbers, some studies include both chemotherapy and radiotherapy, and there are differences from study to study in the timing of samples procured for analysis. For the most part, significantly increased aneuploidy frequencies have been found coincident with chemotherapy for a range of chromosomes during treatment.
The current study's finding of significantly elevated frequencies of sperm aneuploidy in Hodgkin's lymphoma patients prior to chemotherapy is in concordance with previous studies (Robbins et al., 1997; Fait et al., 2001; Frias et al., 2003). The finding of the same phenomenon for disomy 21 in individuals with testicular cancer (not previously reported, to the best of our knowledge) suggests that these findings are real. It is clear from these results that the presence of either cancer type alone has the ability to perturb meiosis for certain chromosomes even before treatment. Indeed, it has been previously documented in both testicular cancer and Hodgkin's lymphoma patients that the cancer itself can have unpredictable effects on fertility as a direct effect of the disease on the testis, with a proportion of males showing impaired spermatogenesis prior to treatment (Fossa et al., 1989; Viviani et al., 1991; Meirow and Schenker, 1995; Lass et al., 1998; Petersen et al., 1999; Rueffer et al., 2001). It has been reported that prior to orchiectomy, testicular cancer patients had sperm counts approximately one-third lower than that seen in normal males (Petersen et al., 1999), believed to be a result of primary gonadal damage (Viviani et al., 1991). Several studies also report an association between Hodgkin's lymphoma and reduced fertility with impaired spermatogenesis in an estimated 66% of males prior to treatment, of which approximately half have diminished sperm counts (Viviani et al., 1991; Rueffer et al., 2001). Examination of the semen parameters within the patient cohort enrolled in this study revealed impaired spermatogenesis and diminished sperm counts in one testicular cancer male (20%) and three Hodgkin's lymphoma males (60%) prior to chemotherapy. The underlying mechanism leading to reduced fertility in Hodgkin's patients is not considered to be a result of primary gonadal damage, but is thought to involve cytokines (Rueffer et al., 2001). However, impaired spermatogenesis is also associated with chronic diseases, especially in those for which a fever is reported (Koentjoro-Soehadi, 1982; Haimov-Kochman et al., 2001; Jung et al., 2001). Approximately 31% of Hodgkin's lymphoma patients report fever and/or drenching night sweats up to 6 months preceding diagnosis (Jose et al., 2005), which could in part explain the reduced fertility noted in some patients. Therefore, it seems that both Hodgkin's lymphoma and testicular cancer can exert a detrimental effect on spermatogenesis, and that the presence of the cancer alone appears to also affect the fidelity of chromosome segregation at meiosis for certain chromosomes. However, the exact mechanism by which these cancers can impair spermatogenesis and meiosis remains to be elucidated.
The current study is in agreement with the majority of published FISH studies: significantly increased aneuploidy frequencies involving all investigated chromosomes were found at 6 months (Robbins et al., 1997; Martin et al., 1999; Frias et al., 2003), and in general, these frequencies declined to pretreatment levels 18–24 months after the initiation of chemotherapy. The significant increase in disomy 13 frequencies found 18–24 months after the initiation of chemotherapy in testicular cancer patients correlates well with previous studies (Martin et al., 1999; De Mas et al., 2001; Thomas et al., 2004). While in agreement with previous studies, this study has revealed that within our cohort of patients of both cancer types, there is a degree of unexplained variability in aneuploidy across time for different chromosomes and, interestingly, an increase in the reciprocal product of non-disjunction for the different aneuploidies is not always found. These observed differences could in theory be due to lab artefact, but in this study, conditions that could account for the variations observed have been removed to the best of our ability. All samples were stored identically, coded prior to shipping for FISH analysis, scored within the same time period by the same investigator and reliable probes from the same source were used for all hybridizations. The fact that in some cases an increase in the reciprocal product of non-disjunction was not observed could in part be explained by anaphase lag (Delhanty, 2005). Although severely infertile oligoasthenoteratozoospermic (OAT) males have much higher aneuploidy frequencies (Tempest and Griffin, 2004), there was no correlation between poor semen parameters and increased aneuploidy as a result of the cancer itself and/or the chemotherapy treatment in the current study. It is therefore likely that the variability in aneuploidy frequencies observed in this study could, in part, be due to unknown individual genetic factors or susceptibilities.
Concurrent investigation of more than one cancer type has enabled us to draw comparisons between findings for the two groups, and studying patients with the same treatment regimen within each group has allowed the elimination of differing treatments as a contributor to observed results. Significant differences which were found in aneuploidy frequencies between cancer types can therefore be considered to be attributed only to the cancer type and/or to treatment for that particular cancer.
In conclusion, it is evident from the data that chemotherapy can induce significantly increased aneuploidy frequencies involving all investigated chromosomes 6 months after the commencement of treatment. The vast majority of these elevated frequencies decline to pretreatment levels around 18 months after the initiation of treatment. Cancer specific differences such as increased aneuploidy frequencies throughout treatment exhibited by Hodgkin's lymphoma patients (compared with testicular cancer and controls) is perhaps not surprising, as different drug treatments and regimens are used in the treatment of these two cancers. Therefore, it is not unreasonable to suggest that the chemotherapy treatment for Hodgkin's lymphoma is more detrimental to the meiotic process, inducing more sperm aneuploidy than testicular cancer treatment. Until the different cancers and treatments have been studied in more detail, the underlying mechanisms of induction and their heritable consequences will remain unknown, since it is likely that they carry different risks. Nonetheless, data from this and previous studies (Robbins et al., 1997; Frias et al., 2003) indicate that because of elevated aneuploidy frequencies prior to and 6 months after the start of chemotherapy, testicular cancer and Hodgkin's lymphoma patients should receive genetic counselling. The elevated aneuploidy frequencies (compared with pretreatment frequencies or controls) observed at the end of this 24 month study period are obviously of clinical concern. The limited number of studies of patients beyond 24 months post-chemotherapy has shown no increased aneuploidy frequency, but these are based on small patient numbers (Martin et al., 1995, 1997b; Robbins et al., 1997; Martin, 1998; Thomas et al., 2004). Clearly, longer term studies are required in the future to determine whether there is an increased risk of producing an aneuploid conceptus after 24 months. Genetic counselling of testicular cancer and Hodgkin's lymphoma patients should include information about the potentially elevated risk of an aneuploid conceptus from sperm cryopreserved prior to chemotherapy and for conceptions up to at least 24 months from the initiation of treatment (although aneuploidy frequencies in Hodgkin's patients return to pretreatment levels after 18 months, they remain significantly higher than control males). This information will assist cancer patients to make informed decisions regarding their future reproductive choices.
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Institute for Human Development, Child and Youth Health of the Canadian Institutes of Health Research.
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The authors would like to thank Dr Cristián O'Flaherty for expert technical assistance. R.H.M. holds a Canada Research Chair in Genetics; H.T. is a recipient of a CIHR Strategic Training Fellowship in Genetics, Child Development and Health, the Petro Canada Young Innovators Award, and the Champion Technologies Award.
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Submitted on July 10, 2007; resubmitted on November 7, 2007; accepted on November 14, 2007.
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